Abstract

Placental microRNAs (miRNAs) regulate the placental transcriptome and play a pathological role in preeclampsia (PE), a hypertensive disorder of pregnancy. Three PE rodent model studies explored the role of placental miRNAs, miR-210, miR-126, and miR-148/152 respectively, by examining expression of the miRNAs, their inducers, and potential gene targets. This review evaluates the role of miR-210, miR-126, and miR-148/152 in PE by comparing findings from the three rodent model studies with in vitro studies, other animal models, and preeclamptic patients to provide comprehensive insight into genetic components and pathological processes in the placenta contributing to PE. The majority of studies demonstrate miR-210 is upregulated in PE in part driven by HIF-1α and NF-κBp50, stimulated by hypoxia and/or immune-mediated processes. Elevated miR-210 may contribute to PE via inhibiting anti-inflammatory Th2-cytokines. Studies report an up- and downregulation of miR-126, arguably reflecting differences in expression between cell types and its multifunctional capacity. MiR-126 may play a pro-angiogenic role by mediating the PI3K-Akt pathway. Most studies report miR-148/152 family members are upregulated in PE. Evidence suggests they may inhibit DNA methylation of genes involved in metabolic and inflammatory pathways. Given the genetic heterogeneity of PE, it is unlikely that a single placental miRNA is a suitable therapeutic target for all patients. Investigating miRNAs in PE subtypes in patients and animal models may represent a more appropriate approach going forward. Developing methods for targeting placental miRNAs and specific placental cell types remains crucial for research seeking to target placental miRNAs as a novel treatment for PE.

Introduction

Preeclampsia (PE) is a hypertensive disorder of pregnancy, with a global estimated incidence of 3–8% [1]. Although its incidence varies substantially around the world, it remains a leading cause of maternal and perinatal morbidity and mortality [2]. PE is defined by the presence of new hypertension and new-onset significant proteinuria or other maternal organ/utero-placental dysfunction occurring at or after 20 weeks of pregnancy [3]. An effective treatment that leads to resolution of maternal complications is delivery of the fetus and placenta, contributing to the body of evidence that the placenta is a necessary and central component of the pathogenesis of PE. As a complex genetic disorder, PE arises from the interaction of environmental and genetic factors, with genetic effects contributing an estimated 50% to its etiology [4,5]. In attempt to identify potential biomarker candidates and elucidate the molecular mechanisms of PE, a host of genome-wide expression profiling studies has identified hundreds of differentially expressed genes in the placentas of preeclamptic patients, highlighting the polygenic nature of PE and essential involvement of the placenta in its pathology [6,7]. Alongside these findings, a number of studies have identified altered microRNA (miRNA) expression profiles in the placentas of patients with PE [8]. In turn, mounting evidence suggests miRNAs precisely regulate the placental transcriptome and alterations in miRNA expression play a key role in the development of PE.

MicroRNAs in preeclampsia

MiRNAs are a class of short, non-coding RNA molecules, approximately 22 nucleotides in length, involved in post-transcriptional regulation of gene expression [9]. Single-stranded mature miRNAs harbor a highly conserved sequence, known as the seed region, which consists of 2–8 nucleotides. The seed region binds via full or partial complementary base pairing to the 3′ untranslated region of messenger RNA (mRNA) of one to hundreds of target genes, inducing translational inhibition or degradation of mRNA [9]. There are now over 2600 miRNAs annotated in the human genome (miRBase v22), and it is estimated that 30–60% of protein coding genes may be subject to miRNA regulation [10,11]. A considerable number of miRNAs are conserved across species [12], indicating their involvement in essential physiological processes. Inactivation of miRNA machinery in vivo induces placental malformation [13] and knockdown of miRNA machinery in ex vivo placental explants leads to aberrant trophoblast proliferation [14], showing the critical role of miRNAs in placental development. Inhibition and overexpression of miRNAs in primary trophoblasts and trophoblast and endothelial cell lines have further demonstrated the ability of miRNAs to modulate placental development and function [15]. In addition, both rodents and primates possess species-specific miRNA clusters that are expressed primarily or exclusively in the placenta and are essential for placental and fetal development [16]. For example, knockout (KO) of the rodent-specific chromosome 2 microRNA cluster in mice leads to severely impaired placental development, embryolethality, and fetal defects [17]. Moreover, members of the primate-specific chromosome 19 miRNA cluster are significantly differentially expressed in preeclamptic patients [18,19], potential biomarkers for PE [20,21], and involved in trophoblast function through modulation of target genes [22,23]. Hence, species-specific placental miRNAs are involved in PE. MiRNAs conserved across species are also dysregulated in the placentas of patients with PE, and in vitro investigations have begun to elucidate the pathological pathways and downstream targets of conserved miRNAs [24–26]. However, studies examining the role of miRNAs in animal models of PE are limited, with only three studies identified in the literature that investigate the role of miR-210, miR-126, and miR-148/152, respectively. Preclinical animal models allow molecular and functional analyses of the disease mechanism not possible in humans and are therefore critical for understanding the role of placental miRNAs in the pathology of PE. Furthermore, comparing the miRNA expression profiles of animal models of PE to that of patients with PE permits evaluation of miRNAs as potential targets for novel treatments. This is particularly relevant given the inconsistency across clinical studies as to which miRNAs are differentially expressed in the placentas of preeclamptic patients and their direction of expression, which may in part be attributed to patient characteristics (such as ethnicity, gestational age, presence or absence of labor, and preterm or term delivery) and differences in experimental methodologies. Hence, animal models provide crucial insight into the miRNAs modulating altered gene expression in the placenta in PE and the pathological mechanisms arising from as well as governing their dysregulation.

Rodent models of preeclampsia

Rodents are valuable animal models for studying the genetics underlying the human placenta in health and disease. The placentas of humans and rodents fall under the same classifications of discoid (referring to its gross morphology) and hemochorial (referring to the fetal epithelium bathing in maternal blood). In addition to commonalities in placental structure and function [27], genome-wide gene expression profiling suggests they share similarities in terms of placental gene expression patterns across pregnancy [28]. Rodents also undergo similar cardiovascular adaptations to those seen in human pregnancies, such as increased glomerular filtration rate and renal plasma flow [29]; reduced sensitivity to Angiotensin II (Ang II) [30]; decreased vascular tone and vasomotion [31]; and elevated cardiac output, stroke volume, and heart rate [32]. Hence, rodents have been ubiquitously utilized as animal models of PE, including through utero-placental ischemia, nitric oxide synthase inhibition, angiogenesis antagonism, inflammatory activation, and renin–angiotensin system stimulation [33]. In support of their use, rodent models commonly display the hallmark features of PE, namely hypertension and proteinuria, in addition to other PE-like symptoms, such as endothelial dysfunction, placental abnormalities, and fetal demise/growth restriction [33].

Animal models are essential to studying PE since the disorder presents almost exclusively in humans, with spontaneous PE otherwise described in only a handful of non-human primates [34–37]. The occurrence of PE in humans and non-human primates is in part attributed to extensive trophoblast invasion leading to abnormal remodeling of maternal spiral arteries that supply the placenta, a pathological process unique to these species [38]. While trophoblast invasion and maternal artery remodeling is common to humans, rats, and mice, trophoblasts invade to a notably lesser extent in rats and mice compared with humans [39]. This highlights one of the major disadvantages of rodent models, namely that PE must be induced, commonly achieved by surgical or pharmacological interventions [33]. Furthermore, differences in cell types and the ensuing mechanisms regulating placental signaling contribute to the distinct placental morphology and placental cellular functions between humans and rodents [39]. These distinguishing features in turn reflect species-specific gene expression patterns in the placenta [28]. Recapitulating the disease in rodents therefore carries limitations and extrapolating findings to humans must be carefully considered. Nonetheless, given the ethical implications of conducting research in human pregnancy, rodents represent a valuable model system for investigating the pathological mechanisms contributing to the development of PE.

Placental microRNAs in rodent models of preeclampsia

Three studies utilizing animal models of PE were conducted in rodents to explore the role of placental miRNAs, miR-210, miR-126, and miR-148/152 respectively, by examining expression of the miRNAs, their regulators, and their gene targets [40–42]. The following review examines the role of miR-210, miR-126, and miR-148/152 in PE by comparing their direction of expression in PE animal model studies to those reported in PE patients. Moreover, cross-examining the expression of regulators and potential gene targets of miRNAs identified in the PE animal model studies with evidence from in vitro studies, other PE animal models, and preeclamptic patients offers comprehensive insight into the genetic components and pathological processes in the placenta that contribute to the disease etiology. Overall, preclinical and clinical studies provide unique evidence of the placental genetic factors involved in PE. Identifying similarities and differences between these studies as well as incorporating evidence from in vitro studies remains crucial to deepen our knowledge of the genetic pathways contributing to the pathogenesis of PE, with the potential to identify targets for novel treatments in PE.

MiR-210

MiR-210 has been implicated in a variety of physiological processes, including cell proliferation, differentiation, metabolism, and apoptosis; cell cycle regulation; mitochondrial function; angiogenesis; neurogenesis; erythropoiesis; and spermatogenesis (reviewed by [43]). Concurrently, its aberrant expression in a range of disease states, such as tumorigenesis, cancer, status epilepticus, cryptorchidism, and cardiovascular diseases (CVDs), has prompted investigations into the role of miR-210 in different pathological processes [43]. MiR-210 is now recognized as a key hypoxia-response factor both in healthy and disease states, underlying its name as the master ‘hypoxamir’, a hypoxia-inducible miRNA [44]. The induction of miR-210 in response to hypoxia has been demonstrated in practically all primary cells and cell lines investigated [45,46], and preclinical and clinical evidence has consistently shown its upregulation in ischemic tissues and conditions [47–50]. In addition to hypoxia, oxidative stress and inflammation mediate miR-210 expression, highlighting that hypoxia-independent mechanisms contribute to the role of miR-210 in physiological and pathological processes [51,52]. Likewise, evidence from animal models used to investigate the role of miR-210 in the pathophysiological processes of PE supports the involvement of both hypoxia-dependent and -independent mechanisms, findings corroborated by preclinical in vitro and in vivo studies and clinical studies in preeclamptic patients.

Only a single PE animal model study investigating the role of miR-210 in PE was identified in the literature. The study utilized mice treated with the toll-like receptor 3 (TLR3) agonist, poly I:C (P-PIC), to induce a preeclamptic phenotype [40,53]. The study found significantly greater placental miR-210 expression in TLR3-induced PE mice as compared with wild-type (WT) mice [40]. Two further preclinical studies have provided indirect evidence of miR-210 involvement in PE through examination of the miRNA and its gene targets in models of gestational hypoxia [54,55], a valuable model for drawing inferences about PE. While gestational hypoxia is not specific to PE and there are differences in the maternal physiological responses to each, high altitude placentas represent valuable models for studying PE (reviewed by [56]). High altitude and PE produce similar molecular changes in the placenta [57], and women living at higher altitudes have an increased risk of developing PE [58–60], highlighting a common pathophysiological impact. In line with the findings from the TLR3-induced PE mouse model, a significant upregulation of miR-210 was reported in the uterine arteries of pregnant sheep residing at high altitude [55]. An increase in miR-210 in these models lies in agreement with the consistent upregulation of miR-210 seen in the placentas (16 studies) and blood (6 studies) of preeclamptic patients (Table 1) and in placentas from high-altitude pregnancies [61]. However, it remains unclear whether altered miR-210 expression is a consequence or cause of PE and a harmful or protective mechanism. Nonetheless, one study found miR-210 was upregulated as early as 12 weeks of pregnancy in preeclamptic patients [62], and another study demonstrated its utility as a potential serum biomarker [63] (Table 1).

Table 1
Studies demonstrating a significant change in miR-210 expression in PE patients compared with healthy pregnant women
StudyType of studyType of PETime of collectionTissue sampleDirection of change
Zhu et al. 2009 [19Microarray
qPCR 
Severe
Mild 
Delivery
Delivery 
Placenta villi
Placenta villi 
Up
Down 
Enquobahrie et al. 2011 [64Microarray and qPCR Diagnosed Delivery 8 maternal and 8 fetal sites Up 
Ishibashi et al. 2012 [65RNA seq and qPCR EO, LO, and superimposed Delivery Placenta Up 
Muralimanoharan et al. 2012 [66qPCR Severe Delivery Placenta villi Up 
Zhang et al. 2012 [67qPCR Mild and severe Delivery Plasma Up 
Anton et al. 2013 [63qPCR Diagnosed Delivery and 15–20 weeks Serum Up 
Betoni et al. 2013 [68Microarray Diagnosed Delivery Placenta Up 
Lalevée et al. 2014 [24qPCR Severe Delivery Placenta Up 
Luo et al. 2014 [69qPCR Severe Delivery Basal plate
Chorionic plate 
Up
n.s. 
Ura et al. 2014 [62Microarray and qPCR Severe 12–14 weeks Serum Up 
Weedon-Fekjær et al. 2014 [70RNA seq EO and LO Delivery Centrally located cotyledon Up 
Xu et al. 2014 [71Microarray
qPCR 
Severe
Severe 
Delivery
Delivery

15–18 weeks and term 
Placenta
Basal plate
Chorionic plate
Plasma 
Up
Up
n.s.
n.s.
 
Jiang et al. 2015 [25Microarray Severe Delivery 8 maternal and 8 fetal sites Up 
Zhang et al. 2015 [72Microarray Severe Delivery Basal plate Up 
Vashukova et al. 2016 [73RNA seq Superimposed Delivery Placenta villi of 8 maternal and 8 fetal sites Up 
Zhou et al. 2016 [26RNA seq and qPCR Diagnosed Delivery Chorionic plate from quadrants and central portion in placenta disc Up 
Adel et al. 2017 [74qPCR Mild and severe Delivery Placenta villi Up 
Gan et al. 2017 [75qPCR Diagnosed Delivery Serum
Urine 
Up
n.s. 
Jairajpuri et al. 2017 [76Microarray Mild and severe Delivery Plasma Up 
Chen et al. 2019 [77qPCR LO Delivery Full thickness placental biopsy Up 
Nejad et al. 2019 [78qPCR Diagnosed Delivery Plasma Up 
Wang et al. 2019 [79qPCR Diagnosed Delivery 3–5 cm from umbilical cord attachment site (chorionic side, full thickness) Up 
StudyType of studyType of PETime of collectionTissue sampleDirection of change
Zhu et al. 2009 [19Microarray
qPCR 
Severe
Mild 
Delivery
Delivery 
Placenta villi
Placenta villi 
Up
Down 
Enquobahrie et al. 2011 [64Microarray and qPCR Diagnosed Delivery 8 maternal and 8 fetal sites Up 
Ishibashi et al. 2012 [65RNA seq and qPCR EO, LO, and superimposed Delivery Placenta Up 
Muralimanoharan et al. 2012 [66qPCR Severe Delivery Placenta villi Up 
Zhang et al. 2012 [67qPCR Mild and severe Delivery Plasma Up 
Anton et al. 2013 [63qPCR Diagnosed Delivery and 15–20 weeks Serum Up 
Betoni et al. 2013 [68Microarray Diagnosed Delivery Placenta Up 
Lalevée et al. 2014 [24qPCR Severe Delivery Placenta Up 
Luo et al. 2014 [69qPCR Severe Delivery Basal plate
Chorionic plate 
Up
n.s. 
Ura et al. 2014 [62Microarray and qPCR Severe 12–14 weeks Serum Up 
Weedon-Fekjær et al. 2014 [70RNA seq EO and LO Delivery Centrally located cotyledon Up 
Xu et al. 2014 [71Microarray
qPCR 
Severe
Severe 
Delivery
Delivery

15–18 weeks and term 
Placenta
Basal plate
Chorionic plate
Plasma 
Up
Up
n.s.
n.s.
 
Jiang et al. 2015 [25Microarray Severe Delivery 8 maternal and 8 fetal sites Up 
Zhang et al. 2015 [72Microarray Severe Delivery Basal plate Up 
Vashukova et al. 2016 [73RNA seq Superimposed Delivery Placenta villi of 8 maternal and 8 fetal sites Up 
Zhou et al. 2016 [26RNA seq and qPCR Diagnosed Delivery Chorionic plate from quadrants and central portion in placenta disc Up 
Adel et al. 2017 [74qPCR Mild and severe Delivery Placenta villi Up 
Gan et al. 2017 [75qPCR Diagnosed Delivery Serum
Urine 
Up
n.s. 
Jairajpuri et al. 2017 [76Microarray Mild and severe Delivery Plasma Up 
Chen et al. 2019 [77qPCR LO Delivery Full thickness placental biopsy Up 
Nejad et al. 2019 [78qPCR Diagnosed Delivery Plasma Up 
Wang et al. 2019 [79qPCR Diagnosed Delivery 3–5 cm from umbilical cord attachment site (chorionic side, full thickness) Up 

EO, early onset; LO, late onset; n.s., not significant; wks, weeks. Time of collection designated ‘delivery’ if not stated in study.

In contrast with the multitude of studies reporting an upregulation, a reduction in miR-210 expression was noted in a study of pregnant mice subject to hypoxia, although the study attributed this to moderate hypoxia exposure [54]. This finding is supported by a study in patients that found a downregulation of miR-210 in patients with mild PE (Table 1) [19]. Hence, higher levels of hypoxia above a certain threshold may drive up miR-210 expression, providing an explanation for the consistent upregulation seen in severe PE. Important to note though is that several studies in mild preeclamptic patients have also observed an increase in miR-210 expression (Table 1) [67,74,76]. Furthermore, exposure of WT and miR-210 KO mice to moderate hypoxia led to an increase in placental weight, and no histological differences were observed between the groups [40]. This demonstrates miR-210 is not essential for normal fetal placental growth under moderately hypoxic conditions. It also suggests that moderate hypoxia does not induce the harmful effects potentially associated with an upregulation of miR-210 arising from severe hypoxia.

In a further two further studies in preeclamptic patients, although a significant increase in miR-210 was seen in the basal plate, a non-significant trend toward downregulation of miR-210 was evident in the chorionic plate [69,71] (Table 1). Unlike the basal plate, which primarily comprises maternal tissue, the chorionic plate consists solely of fetal tissue, including fetal blood vessels, trophoblasts, and stroma tissue. Varying proportions of maternal and fetal tissue underlie the distinct cell types, morphology, and physiological roles of the different layers of the placenta. In turn, there are variations in gene expression between placental layers [80,81] and trophoblast cell types [82], supporting the findings of heterogeneous miRNA expression. Site-specific differences in miR-210 expression across the placenta therefore probably reflect the unique placenta genome, which consists of maternal and fetal genes and their differing contributions to each layer as well as a variety of cell types. Overall, despite the diverse genetic makeup of the placenta, the majority of preclinical and clinical studies point toward an upregulation of miR-210 in PE. While inhibiting miR-210 expression in patients with severe PE may therefore represent a potential treatment strategy, precise targeting may be required to achieve a therapeutic benefit due to varied miR-210 expression across the placenta.

Inducers of MiR-210

To identify drivers of elevated miR-210 expression in PE, the study investigating the role of miR-210 in a TLR3-induced mouse model of PE examined the expression of transcription factors, hypoxia-inducible factor 1 (HIF-1) α and nuclear factor-κB transcriptional factor (NF-κB) p50, finding significantly increased placental expression of both factors [40]. HIF-1 is a key mediator of the cellular response to hypoxia. Under hypoxic conditions, the inducible HIF-1α subunit is stable, allowing it to form a dimer with the constitutive HIF-1β subunit and bind to hypoxia response elements (HREs) of target genes or miRNAs and regulate their expression [83]. In turn, this affects a diverse array of physiological and pathophysiological pathways (reviewed by [83]). Although HIF-1α and -2α KO mice demonstrate the essential involvement of HIFs in placental vascularization and trophoblast differentiation [84], overexpression of HIF-1 α has been shown to induce a preeclamptic phenotype in pregnant mice [85], supporting its role in the pathogenesis of PE. A growing number of studies suggest placental hypoxia modulates HIF-1α expression, mediating downstream targets involved in PE, including soluble vascular endothelial growth factor receptor-1 (sFlt-1) [86], transforming growth factor beta [87], and endoglin [88]. In addition to hypoxia, immune responses mediated by toll-like receptors may drive differential gene expression in PE. Kopriva et al. [40] found that, in TLR3-KO mice treated with the TLR3 agonist, P-PIC, the elevation of miR-210, HIF-1α, and NF-κBp50 was ameliorated, indicating an important role for TLR3 activation. In addition to stimulation of TLR3 inducing a PE phenotype in mice and rats [53,89], an upregulation of TLR3 has been observed in PE patients [90], supporting the hypothesis that excessive activation of TLR3 may play an important role in the development of PE. Double-stranded RNA, arising from virus replication or necrotic, apoptotic, or stressed cells, leads to TLR3 activation [91]. TLR3 activates two key pathways involving NF-κB and interferon regulatory factor 3, which subsequently activate pro-inflammatory cytokines and Type 1 interferons, respectively [92,93]. The NF-κB transcription factor family consists of five members divided into two subfamilies: the NF-κB proteins, NF-κB1 (p50) and NF-κB2 (p52), and Rel proteins, RelA (p65), RelB, and c-Rel, which can form homo- and heterodimers that bind to DNA target sites and induce transcription of target genes [94]. In trophoblasts exposed to the TLR3 ligand, P-PIC, and in placental explants subject to hypoxia-reoxygenation, an increase in NF-κBp50 was associated with upregulation of genes known to be involved in PE, namely the anti-angiogenic factor sFLT-1 [93], pro-inflammatory enzyme cyclooxygenase-2, and pro-inflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin 1 β (IL-1β) [95]. Dysregulation of HIF-1α and NF-κBp50 arising from hypoxia and/or immune- mediated responses and a concurrent modulation of target genes suggests the transcription factors play a key role in the pathology of PE, with miR-210 representing a potential target (Figure 1).

Supporting and contradicting evidence of proposed genetic components and pathological processes involved in PE based on PE rodent model study investigating the role of placental miR-210

Figure 1
Supporting and contradicting evidence of proposed genetic components and pathological processes involved in PE based on PE rodent model study investigating the role of placental miR-210

miR-210, microRNA 210; HIF-1 α, hypoxia-inducible factor 1 α; HIF-2α, hypoxia-inducible factor 2 α; NF-κBp50, nuclear factor-κB transcriptional factor p50; STAT6, signal transducer and activator of transcription 6; IL-4, interleukin-4; IL-10, interleukin 10; Th2, T-helper type 2; PE, preeclampsia; EO, early-onset; LO, late onset; TLR3, toll-like receptor 3; HUVECs, human umbilical vein endothelial cells; RUPP, reduced uterine perfusion pressure.

Figure 1
Supporting and contradicting evidence of proposed genetic components and pathological processes involved in PE based on PE rodent model study investigating the role of placental miR-210

miR-210, microRNA 210; HIF-1 α, hypoxia-inducible factor 1 α; HIF-2α, hypoxia-inducible factor 2 α; NF-κBp50, nuclear factor-κB transcriptional factor p50; STAT6, signal transducer and activator of transcription 6; IL-4, interleukin-4; IL-10, interleukin 10; Th2, T-helper type 2; PE, preeclampsia; EO, early-onset; LO, late onset; TLR3, toll-like receptor 3; HUVECs, human umbilical vein endothelial cells; RUPP, reduced uterine perfusion pressure.

HIF-1α induces miR-210 expression via binding to a HRE region of the miR-210 promoter, a sequence highly conserved across species, including mice, rats, and humans [96]. In vitro studies have shown direct regulation of miR-210 by HIF-1α during hypoxia in trophoblastic JAr cells [67] and human umbilical vein endothelial cells (HUVECs) [97,98]. In addition, direct regulation of miR-210 by the HIF-1α isoform, HIF-2α, has been observed in the trophoblastic BeWo cell line [24]. Studies have also provided broader evidence of a hypoxia-dependent induction of miR-210 by demonstrating upregulation of the miRNA in response to hypoxia exposure in practically all primary cells and cell lines, which includes trophoblast-derived cell lines [61,65,99], primary trophoblasts [66,67], and ex vivo uterine arteries [55]. Collectively, these studies support that hypoxia, potentially through induction of HIF-1α, stimulates miR-210 expression (Figure 1).

PE animal models and clinical studies in preeclamptic patients reporting an increase in HIF-1α further corroborate the involvement of hypoxia in PE and explain the consistently observed upregulation of miR-210 in PE patients. Numerous PE rodent models exhibit elevated placental levels of HIF-1α [100–105]. In an Ang II infused superimposed PE rat model, there was no difference observed in placental HIF-1α in comparison with control stroke-prone spontaneously hypertensive (SHRSP) rats [106]. However, elevated levels of HIF-1α in SHRSP placentas have previously been reported, thus potentially masking increases in HIF-1α levels when used as a control [107]. Finally, overexpression of HIF-1α in C57BL/6J pregnant mice produced a PE phenotype [85]. With respect to PE patients, a plethora of clinical studies show higher protein levels of HIF-1α in third trimester placentas [66,108–115]. Significantly greater levels have also been identified in blood as early as weeks 6–23 of pregnancy [116] and in placentas from high-altitude pregnancies [117]. In studies that found no significant difference in HIF-1α levels in the placentas of PE patients, a significant upregulation of HIF-2α was noted [118,119]. These clinical findings raise the possibility that placental hypoxia plays a causal role in the development of PE, in part through upregulation of HIF-α proteins, which in turn leads to dysregulation of downstream targets, including miR-210 (Figure 1).

With regards to NF-κBp50, in vitro studies report the transcription factor binds to the miR-210 promoter in primary trophoblasts and JAr cells [67,120], supporting the increased NF-κBp50 and miR-210 levels seen in the placentas of the TLR3-induced PE mouse model [40]. N (gamma)-nitro-L-arginine methyl ester (L-NAME)-induced preeclamptic rats also display enhanced NF-κB activation [121] and lipopolysaccharide (LPS)-induced preeclamptic rats show elevated levels of NF-κBp65 [122,123]. In agreement with the general trend toward an upregulation of NF-κB transcriptional factors, results of immunohistochemical studies conducted in placentas from pregnancies complicated with PE show higher expression of NF-κBp50 [124,125] and NF-κBp65 [125–127]. Furthermore, in silico comparative promoter analyses of data from microarray studies examining altered gene expression in placentas from PE patients found a greater number of NF-κBp50 transcriptional factor binding sites in the promoter sequences of dysregulated genes [128,129]. Enhanced NF-κBp50 expression and activation in the placenta therefore probably plays a role in the pathology of PE and contributes to the upregulation of miR-210 in PE (Figure 1).

Gene targets of MiR-210

Kopriva, et al. [40] examined gene targets of miR-210 in the PE mouse model, namely signal transducer and activator of transcription 6 (STAT6) and interleukin 4 (IL-4). IL-4 is a cytokine that plays a key role in regulating the immune system. Binding of IL-4 to its receptor activates STAT6, a mediator of T-helper type 2 (Th2) cell differentiation [130]. Activation of STAT6 by IL-4 promotes expression of GATA binding protein 3 (GATA3), a master regulator of Th2 cell differentiation, which binds and enhances expression of the anti-inflammatory Th2 cytokines [130]. An imbalance between T-helper type 1 (Th1) and Th2 cytokines is one theory underlying the pathology of PE [131,132]. Studies have found elevated levels of pro-inflammatory Th1 cytokines in preeclamptic patients in contrast with the dominant Th2 cytokine profile in healthy pregnancy [133–135]. Modulation of genes involved in Th2 differentiation by miR-210 provides insight into the mechanisms governing the reported shift in the immune profile of preeclamptic patients and demonstrates a role for the miRNA in the pathology of PE.

In a trophoblastic Swan 71 cell line transfected with miR-210, STAT6 was identified as a downregulated gene [136]. Previous studies investigating STAT6 expression in the placenta and maternal serum also found a reduction in STAT6 protein levels in preeclamptic patients [115,137]. This is in line with the reported downregulation of the protein levels of the miR-210 predicted target STAT6 in the placentas of TLR3-induced PE mice [40]. In addition to reduced STAT6 expression, Kopriva et al. [40] observed significantly downregulated placental IL-4 levels. In a separate study, the group showed IL-4 deficiency in mice produced a mild PE phenotype [138]. Subsequently, they found that IL-4 treatment and IL-4/ interleukin 10 (IL-10) co-treatment was able to significantly reduce blood pressure and prevent endothelial dysfunction in a TLR3-induced PE mouse model [139]. Another group utilizing IL-10 KO mice exposed to hypoxia to induce severe preeclampsia showed recombinant IL-10 restored blood pressure, proteinuria levels, and fetal weight to physiological values [140]. In reduced uterine perfusion pressure rats, another group reported IL-4 supplementation significantly improved blood pressure and normalized uterine artery resistance index [141]. Stimulating anti-inflammatory Th2 cytokines to confer therapeutic benefit in hypoxia- and immune-based preclinical models of PE suggests their downregulation, in part driven by miR-210 inhibition, may contribute to hypoxia- and immune-related pathological processes in PE. However, studies investigating IL-4 expression in placentas of PE patients have produced conflicting results. In support of the findings of Kopriva et al. [40], demonstrating a downregulation of IL-4 in the TLR3-induced PE mouse model, one study found IL-4 was lower in placental tissue, maternal serum, and cord blood in PE patients when compared with normotensive controls [142]. These findings stand in contrast to studies that showed no difference in placental IL-4 expression in preeclamptic patients [143,144] and a study in which IL-4 could not be detected [145]. However, these studies observed a decrease in other Th2 cytokines and their transcription factors [144,145]. Altogether, evidence supports a role for reduced Th2 cytokine production in PE, which may in turn be subject to miR-210 modulation (Figure 1).

MiR-126

MiR-126 is abundantly expressed in endothelial cells (ECs) [146,147] and known to play an important role in vascular homeostasis through regulation of angiogenesis, vasculogenesis, and inflammation (reviewed by [148]). Deletion of miR-126 in mice has shown to induce embryolethality in 40–50% of cases, with embryos displaying signs of severe systemic edema and hemorrhages, and surviving adult mice exhibiting impaired angiogenesis under physiological conditions and post-injury [146,149]. In zebrafish, knockdown of miR-126 leads to abnormalities in circulation and vascular morphology [150]. Overall, this demonstrates that miR-126 plays an important role in vascular development during embryogenesis and subsequently in maintaining vascular integrity in adulthood with respect to endothelial function and post-injury repair. In further support of its protective and proangiogenic role, the downregulation of miR-126 has been reported in a number of CVDs, including atherosclerosis [151], ischemic stroke [152], heart failure [153], atrial fibrillation [153], coronary artery disease [154], and diabetes [155], with growing interest in its role as a biomarker. However, studies in different cell types, animal models, and diseases, most notably autoimmune diseases and cancer, show that miR-126 also exhibits antiangiogenic effects [156,157]. MiR-126 appears to play a number of roles often antagonistic in nature from proatherogenic [158] to antiatherogenic [159], from tumor suppressor [160] to inducer [161], and from regulator of HSC quiescence to stimulator of HSC activation [162], demonstrating its multi-regulatory capabilities within specific cell types.

The context-dependent function of miR-126 is reflected by its expression in a range of cell types besides ECs, with miR-126 identified in endothelial progenitor cells (EPCs) [163], epithelial cells [164], hematopoietic stem and progenitor cells [162], platelets [165], and several types of cancer [166–168] and immune cells [169,170]. Furthermore, the diverse roles of miR-126 in part arises from the number of factors regulating its expression. Described by some as a ‘mechanomir’, miR-126 expression has shown to be downregulated by hypoxia [171] and both stimulated [172] and inhibited [158] by laminar shear stress. Its divergent properties are also attributable to miR-126 activating the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathway, an intracellular signal transduction pathway that regulates a host of cellular processes, such as cell metabolism, proliferation, survival, growth, autophagy, and angiogenesis [173]. Phosphatidylinositol 3-kinase regulatory subunit 2 (PIK3R2) has been validated as a target of miR-126 using reporter constructs in a number of cells, including ECs [150], cancer cells [174–176], rheumatoid arthritis synovial fibroblasts [163,177], and EPCs [178,179]. Preclinical studies investigating miR-126 in the placenta suggest that miR-126 plays an important protective angiogenic role through regulation of the PI3K-Akt pathway in PE, although studies in preeclamptic patients provide conflicting results regarding its direction of expression (Figure 2).

Supporting and contradicting evidence of proposed genetic components and pathological processes involved in PE based on PE rodent model study investigating the role of placental miR-126

Figure 2
Supporting and contradicting evidence of proposed genetic components and pathological processes involved in PE based on PE rodent model study investigating the role of placental miR-126

miR-126, microRNA 126; PIK3R2, phosphatidylinositol 3-kinase regulatory subunit 2; PI3K, phosphatidylinositol 3-kinase; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; pAkt, phosphorylated Akt; VEGF, vascular endothelial growth factor; Ang I, Angiotensin I; sEng, soluble endoglin; sFflt-1, soluble vascular endothelial growth factor receptor-1; PE, preeclampsia; LO, late-onset; EO, early-onset; HUVECs, human umbilical vein endothelial cells; L-NAME, N (gamma)-nitro-L-arginine methyl ester; LPS, lipopolysaccharide.

Figure 2
Supporting and contradicting evidence of proposed genetic components and pathological processes involved in PE based on PE rodent model study investigating the role of placental miR-126

miR-126, microRNA 126; PIK3R2, phosphatidylinositol 3-kinase regulatory subunit 2; PI3K, phosphatidylinositol 3-kinase; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; pAkt, phosphorylated Akt; VEGF, vascular endothelial growth factor; Ang I, Angiotensin I; sEng, soluble endoglin; sFflt-1, soluble vascular endothelial growth factor receptor-1; PE, preeclampsia; LO, late-onset; EO, early-onset; HUVECs, human umbilical vein endothelial cells; L-NAME, N (gamma)-nitro-L-arginine methyl ester; LPS, lipopolysaccharide.

Two studies identified in the literature have investigated the placental role of miR-126 in vivo. Following in vitro investigations in EPCs, where overexpression of miR-126 was shown to stimulate EPC proliferation, differentiation, and migration [163], Yan et al. [163] examined the effects of mimicking or silencing miR-126 in the placentas of pregnant rats. Administration of agomir-126 led to an increase in microvessel density and an increase in the size and weight of placentas and fetuses. In agreement, antagomir‐126 administration led to a reduction in microvessel density and a reduction in the size and weight of placentas and fetuses, suggesting a role for miR-126 in placental angiogenesis. These findings prompted the study that investigates the role of miR-126 in a PE animal model and examines its potential as a therapeutic target for PE [41]. Administration of L-NAME to induce a preeclamptic phenotype, demonstrated by elevated systolic blood pressure (SBP) and higher levels of urinary protein, led to a reduction in miR-126 [41]. Administration of agomir-126 led to a reduction in blood pressure, significantly greater placental and fetal weight, enhanced microvessel density, and a higher proportion of live pups, suggesting elevating levels of miR-126 in PE may represent a therapeutic approach to counteract lower levels of miR-126 in PE. However, clinical studies provide conflicting results as to the direction of miR-126 expression in the placenta in preeclamptic patients. While three studies showed a reduction in miR-126 expression in the placentas of preeclamptic patients, two studies detected an increase in expression (Table 2). These opposing findings are arguably not due to differences between subtypes of PE since miR-126 was reported as both up- and downregulated in severe PE patients. It is possible though that the contrasting results reflect differences in expression among different cell types and thus the multi-functional capacity of miR-126. Furthermore, even within subpopulations, PE patients may display diverse genetic signatures, highlighting the difficulty in deciphering the genetics of PE [180]. Despite the therapeutic benefit of increasing placental miR-126 expression in an L-NAME rat model of PE, it remains difficult to discern whether the same therapeutic benefits would translate to patients. Nonetheless, comparing data from animal models with patients provide insight into the clinical relevance of miRNAs and genes under investigation.

Table 2
Studies demonstrating significant change in miR-126 expression in PE patients compared with healthy pregnant women
StudyType of studyType of PETime of collectionTissue sampleDirection of change
Hu et al. 2009 [181Microarray Severe LO Delivery Chorionic tissue from the central part of the placenta Up 
Yan et al. 2013 [163qPCR Diagnosed Delivery Placenta Down 
Hong et al. 2014 [182qPCR Diagnosed Delivery Chorionic tissue from the central part of the placental maternal phase Down 
Ura et al. 2014 [62Microarray and qPCR Severe 12-14 weeks Serum Down 
Jiang et al. 2015 [25Microarray Severe Delivery 8 maternal and 8 fetal sites Down 
Yang et al. 2015 [183RNA seq Mild and severe Delivery Placenta and plasma Up 
Xu et al. 2019 [184In situ hybridization Diagnosed Delivery Systemic vascular endothelium from subcutaneous adipose tissue Down 
StudyType of studyType of PETime of collectionTissue sampleDirection of change
Hu et al. 2009 [181Microarray Severe LO Delivery Chorionic tissue from the central part of the placenta Up 
Yan et al. 2013 [163qPCR Diagnosed Delivery Placenta Down 
Hong et al. 2014 [182qPCR Diagnosed Delivery Chorionic tissue from the central part of the placental maternal phase Down 
Ura et al. 2014 [62Microarray and qPCR Severe 12-14 weeks Serum Down 
Jiang et al. 2015 [25Microarray Severe Delivery 8 maternal and 8 fetal sites Down 
Yang et al. 2015 [183RNA seq Mild and severe Delivery Placenta and plasma Up 
Xu et al. 2019 [184In situ hybridization Diagnosed Delivery Systemic vascular endothelium from subcutaneous adipose tissue Down 

LO, late onset; Time of collection designated ‘delivery’ if not stated in study.

Gene targets of MiR-126

In the study by Yan et. al [41] examining preeclamptic rats with reduced miR-126 expression, mRNA and protein levels of PIK3R2 were significantly greater while phosphorylated Akt (pAkt) and protein kinase B (PKB), also known as Akt, were significantly lower in preeclamptic rats compared with rats administered with agomir-126. There are three classes of phosphatidylinositol 3-kinase (PI3K) enzymes (class I, II, and III). Class IA enzymes consist of two domains: a catalytic and a regulatory subunit. PIK3R2 encodes the p85β regulatory subunit that represses PI3K activation by inhibiting its catalytic subunit, p110. PI3K is primarily activated by phosphorylated receptor tyrosine kinases in response to extracellular signals that abolish p85β inhibition. Activation of PI3K stimulates signal transduction pathways that lead to phosphorylation of Akt, a serine/threonine protein kinase [185]. Once activated, Akt modulates the function of a wide variety of target proteins in both the cytoplasm and nucleus and thus a broad array of cellular functions. Vascular endothelial growth factor (VEGF) mediated angiogenesis has found to be stimulated by miR-126 in endothelial cells through inhibition of sprouty related EVH1 domain containing 1 (SPRED1) and PIK3R2, which negatively regulate extracellular signal–regulated kinase (ERK) and Akt phosphorylation, respectively [146,150]. In addition, VEGF and Angiotensin I (Ang I) induction of miR-126 leading to inhibition of PIK3R2 and enhanced phosphorylation of Akt has been shown to play a role in promoting endothelial cell survival and sprouting [186]. MiR-126 has also been reported to stimulate VEGF expression in trophoblast cells, and lower levels of placental miR-126 in PE patients were associated with decreased VEGF placental expression [182]. Hence, the proangiogenic effects of miR-126 mediated via the PI3K-Akt pathway may be altered in PE (Figure 2).

In an earlier study, Yan et al. [163] utilized miRNA mimics and inhibitors to investigate PIK3R2, PI3K, Akt, and pAKT as targets of miR-126 in EPCs. A miR-126 inhibitor induced a significant increase in mRNA and protein levels of PIK3R2 and significant decrease in the levels of PI3K, pAkt, and Akt, reflecting the results observed in the L-NAME preeclamptic rat model with reduced miR-126 expression [41]. A reduction in pAkt was identified in a different study in L-NAME-induced preeclamptic rats, which found increased sFlt-1 and decreased VEGF placental expression [187]. Reduced pAkt levels were also reported in a study in LPS-induced preeclamptic mice, which displayed an increase in pro-inflammatory cytokines, TNF-α, IL-1β and interleukin-6, and placental chemokines [188]. These findings support involvement of the PI3K/Akt pathway in PE through inhibiting angiogenic and promoting inflammatory processes (Figure 2). It should be noted though that a separate study in L-NAME preeclamptic rats reported an upregulation of placental PI3K and pAkt [189], suggesting that the PI3K/Akt pathway in PE may be modulated by an array of factors.

MiR-126 has also been the subject of clinical studies; an initial study by Yan et al. [163] found a decrease in miR-126 levels in the placentas of PE patients as well as an upregulation of PIK3R2 and downregulation of PI3K, Akt, and pAkt mRNA and protein levels. In agreement, Khaliq et al. [190] reported lower protein levels of placental PI3K, Akt, and pAkt in preeclamptic placentas and a significant negative correlation between the proteins and several serum miRNAs, miR-222, miR-29a, and miR-181a, providing supporting evidence of a link between the PI3K/Akt pathway and miRNAs in PE. Reduced pAkt was seen in a further two studies in PE patients, which showed inhibition of PI3K/Akt in HUVECs stimulated the release of the anti-angiogenic factor soluble endoglin (sEng) [191,192]. One of the studies identified an association between lower pAKT and elevated circulating sEng in patients [191]. Overall, these findings suggest reduced activation of the PI3K/Akt pathway may contribute to the pathology of PE (Figure 2).

However, in placental explants and primary trophoblasts, inhibition of PI3K/Akt did not induce release of sEng [192]. Furthermore, in a trophoblastic JEG-3 cell line, inhibition of PI3K/Akt led to decreased expression of the anti-angiogenic factor sFLT-1 and increased or unchanged expression of the angiogenic factors, VEGF and placental growth factor [193]. This evidence suggests the PI3K/Akt pathway may exhibit cell-dependent effects, with its aberrant expression contributing to either pathological or protective processes depending on cell type. In contrast with the findings of Yan et al. [163], an upregulation of PI3K and Akt has been reported in the placentas of severe preeclamptic patients [193], indicating that, in addition to cell-dependent effects, genetic diversity in PE may underlie differences in PI3K/Akt pathway regulation [193]. One study observed a downregulation of Akt only in preeclamptic patients delivering before 34 weeks but not after [194], and another reported no difference in Akt levels compared with healthy controls [195]. It should be noted though, basal state was measured, and differences may only occur when Akt is stimulated [195]. Overall, there is evidence to support that a reduction of miR-126 in PE leading to an increase in PIK3R2 and decrease in the levels of PI3K, pAkt, and Akt regulates angiogenic and inflammatory processes (Figure 2). Evidence contradicting this direction of expression of miR-126 and its gene targets demonstrates the genetic diversity of PE and again highlights the issue of targeting miR-126 as a treatment for PE, particularly given the cell-dependent effects of miR-126 and the PI3K/Akt pathway.

MiR-148/152

The miR-148/152 family, consisting of miR-148a, miR-148b, and miR-152, plays an important role in regulating immune-related processes and is implicated in the development and progression of multiple types of cancer, autoimmune disorders, and chronic inflammatory diseases (reviewed by [196]). In their mature form, miRNA family members share a common seed sequence and hence target orthologous genes [196]. For example, DNA methyl‐transferase 1 (DNMT1) was experimentally validated as a target of miR-148a in gastric cancer cells [197], miR-148b in lung cancer cells [198], and miR-152 in ovarian [199] and liver cancer cells [200], in each of which overexpression of the miRNAs induced tumor suppressive effects. In turn, the studies reported a downregulation of miR-148/152 family members in the cancerous tissues and/or cells, coinciding with the consistently reported overexpression of DNMT1 in each cancer type [201–204]. In contrast, the miR-148/152 family also demonstrate oncogene capabilities, indicating the family of miRNAs can modulate targets and processes in a cell-specific manner. For example, miR-148a was found to be upregulated in patients with hepatocellular carcinoma [205], and in vitro experiments demonstrated its ability to inhibit a tumor suppressor gene and stimulate cell growth, viability, and migration [205]. In addition to cancerous tissue, evidence suggests that the miR-148/152 family is involved in regulating placental development during pregnancy [206–208]. In trophoblast cells, all three miRNA family members target human leukocyte antigen-G (HLA-G) [206–208]. HLA-G plays an essential immunosuppressive role in mediating the maternal immune tolerance to the fetus by acting as an inhibitory ligand of maternal natural killer cells [209]. It is therefore postulated that reduced expression of miR-148/152 family members in the placenta in a healthy pregnancy may confer a protective effect by permitting sufficient HLA-G expression [206,208]. Correspondingly, evidence from preeclamptic animal models and patients points toward an upregulation of miR-148/152 family members inducing dysregulation of target genes and contributing to the pathogenesis of PE.

The role of miR-148/152 in PE has been investigated in two preeclamptic animal model studies in both of which Sprague Dawley rats were administered L-NAME [42,210]. Yang et al. [42] found miR-148a and miR-152 were significantly upregulated in the placentas of preeclamptic rats, which showed a significant increase in blood pressure and urinary protein as well as pathological placental changes, although no significant difference in fetal weight was observed. Zhang et al. [210] also observed that miR-152 was significantly upregulated, though it should be noted that a PE phenotype was not validated. In terms of miR-152 in preeclamptic patients, two studies reported significantly increased expression in the placenta [19,25], and one study reported increased expression in serum [62] (Table 3). For miR-148a, one study found an upregulation [26] and one study a downregulation [211] in preeclamptic placentas (Table 3). These studies were conducted in the chorionic plate and decidua-derived mesenchymal stem cells respectively, raising the possibility that dysregulation of miR-148a in PE may differ between placental cell types and/or layers, modulate different gene targets, and therefore contribute to pathological processes and/or confer protective effects. Although members of the miR-148/152 family share a common seed sequence, differences in their non-seed sequence may account for targeting of different mRNAs [196]. Hence, the observed upregulation of miR-152 in mild and severe patients and different areas of the placenta, as well as in animal models of PE, may indicate inhibition of miR-152 as a potential therapeutic strategy for PE. However, additional studies across PE subpopulations and placental layers are required to validate miR-152 as an upregulated placental miRNA in PE.

Table 3
Studies demonstrating significant change in miR-148/152 expression in PE patients compared with healthy pregnant women
StudyType of studyType of PETime of collectionTissue sampleDirection of change
miR-148a      
Zhao et al. 2014 [211Microarray Severe LO Delivery Decidua derived MSCs Down 
Zhou et al. 2016 [26RNA seq and qPCR Diagnosed Delivery Chorionic plate from quadrant and central portion in placenta disc Up 
miR-152      
Zhu et al. 2009 [19Microarray and qPCR Mild and severe Delivery Placenta villi Up 
Ura et al. 2014 [62Microarray Severe 12–14 weeks Serum Up 
Jiang et al. 2015 [25Microarray Severe Delivery 8 maternal and 8 fetal sites Up 
StudyType of studyType of PETime of collectionTissue sampleDirection of change
miR-148a      
Zhao et al. 2014 [211Microarray Severe LO Delivery Decidua derived MSCs Down 
Zhou et al. 2016 [26RNA seq and qPCR Diagnosed Delivery Chorionic plate from quadrant and central portion in placenta disc Up 
miR-152      
Zhu et al. 2009 [19Microarray and qPCR Mild and severe Delivery Placenta villi Up 
Ura et al. 2014 [62Microarray Severe 12–14 weeks Serum Up 
Jiang et al. 2015 [25Microarray Severe Delivery 8 maternal and 8 fetal sites Up 

LO, late onset; MSCs, mesenchymal stem cells; Time of collection designated ‘delivery’ if not stated in study.

Gene targets of MiR-148/152

The study investigating miR-148/152 in the L-NAME preeclamptic rat model that provides evidence of a PE phenotype also examined the expression of DNMT1, a gene target of miR-148/152, and fatty acid-binding protein 4 (FABP4), a gene target of DNMT1 [42]. Trophoblast cells incubated with L-NAME stimulated miR-148/152 and inhibited DNMT1 expression [42]. Reduced DNMT1 expression was associated with hypomethylation of FABP4 and thus increased FABP4 expression [42]. In line with these findings, a significant decrease in DNMT1 and increase in FABP4 mRNA and protein was observed in the placentas of L-NAME-induced PE rats and higher protein levels of FABP4 were seen in their sera [42]. DNMT1 belongs to the family of DNA methyltransferase enzymes that establish and maintain DNA methylation patterns [212]. DNA methylation is a major epigenetic mechanism involved in regulating gene expression. DNMT1 catalyses the addition of methyl groups to CpG islands located in the promoter region of a number of genes [212]. This prevents binding of transcription factors to the promoter and therefore primarily leads to silencing of gene expression [212]. Altered DNA methylation in the placentas of PE patients has been investigated extensively. Studies have examined its potential as a biomarker for PE [213] and the association between DNA methylation with clinical manifestations of PE [214]. Moreover, novel genes and miRNAs with differentially methylated regions in PE have been identified, and genes and miRNAs previously detected as differentially expressed in PE have been validated as differentially methylated [215–221]. Furthermore, an in vivo study investigating two mouse models of PE found that elevating placental adenosine caused placental DNA hypomethylation and produced a PE phenotype [222]. When placental adenosine was normalized to physiological levels, placental DNA methylation was restored and ameliorated the PE phenotype [222]. Collectively, these studies support a key involvement of DNA methylation and dysregulation of genes and miRNAs in the pathology of PE. One such target may be FABP4, which belongs to the family of fatty acid binding proteins that play a role in regulating lipid trafficking and cellular responses to lipids [223]. FABP4 is predominantly expressed in adipocytes and macrophages, in turn mediating inflammatory and metabolic pathways, such as regulating lipolysis and acting as a fatty acid chaperone [223]. High levels of circulating FABP4 have been identified in obesity [224], Type 2 diabetes [225], insulin resistance [226], hypertension [227], and atherosclerosis [228] as well as in gestational diabetes [229], gestational hypertension [230], and PE [231,232]. Hence, the miR-148/152 family may contribute to PE via modulation of DNA methylation patterns that leads to aberrant expression of downstream targets involved in metabolic and immune pathways (Figure 3).

Supporting and contradicting evidence of proposed genetic components and pathological processes involved in PE based on PE rodent model study investigating the role of the placental miR-148/152 family

Figure 3
Supporting and contradicting evidence of proposed genetic components and pathological processes involved in PE based on PE rodent model study investigating the role of the placental miR-148/152 family

miR-148/152, microRNA 148/152; miR-148, microRNA 148; miR-152, microRNA 152; DNMT1, DNA-methyltransferase 1; FABP4, fatty acid-binding protein 4; L-NAME, N (gamma)-nitro-L-arginine methyl ester; BPA, Bisphenol A; HREs, hypoxia response elements; HLA-G, human leukocyte antigen-G; HDL, high density lipoprotein.

Figure 3
Supporting and contradicting evidence of proposed genetic components and pathological processes involved in PE based on PE rodent model study investigating the role of the placental miR-148/152 family

miR-148/152, microRNA 148/152; miR-148, microRNA 148; miR-152, microRNA 152; DNMT1, DNA-methyltransferase 1; FABP4, fatty acid-binding protein 4; L-NAME, N (gamma)-nitro-L-arginine methyl ester; BPA, Bisphenol A; HREs, hypoxia response elements; HLA-G, human leukocyte antigen-G; HDL, high density lipoprotein.

In agreement with the findings by Yang et al. [42], a separate study in L-NAME-induced PE rats also reported a downregulation of DNMT1 in placentas and in hypoxia-treated trophoblasts [233]. In contrast, a study examining PE-like mice exposed to Bisphenol A (BPA) found a significant elevation in DNMT1 placental protein levels and an increase in DNMT1 expression in HTR-8/SVneo trophoblast cells exposed to BPA [234]. HTR-8/SVneo and JEG3 cells exposed to hypoxia also exhibited increased DNMT1 mRNA and protein levels [235]. An overexpression of DNMT1 is similarly seen in several clinical studies in preeclamptic placentas [235–237]. A separate study stratified preeclamptic patients into early onset (EO) and late onset (LO)PE detected significantly higher DNMT1 expression only in EO placentas [219]. Furthermore, a study that conducted DNA methylation analysis on candidate genes in preeclamptic placentas identified two CPG sites within DMNT1, one which differed between EOPE and LOPE patients as compared with a control group and one that only differed between EOPE and controls [238]. This suggests that differences in DMNT1 expression may be attributed to diverse PE genotypes. As previously identified, differences in the direction of expression of miR-148/152 family members may account for differences in the expression of DNMT1. Moreover, given the evidence of hypoxia and BPA exposure inducing DNMT1 expression in trophoblast cells, other factors may override the inhibitory effects of the miR-148/152 family on DNMT1 expression. In line with this, hypoxia-induced upregulation of DNMT1 in cardiac fibroblast cells was shown to be regulated by the transcription factor, HIF-1α [239]. Nonetheless, certain evidence suggests the miR-148/152 family may contribute to the development of PE by modulating DNA methylation (Figure 3).

Concerning FABP4, a significant increase in mRNA and protein levels was seen in L-NAME- treated HTR-8/SVneo trophoblast cells as well as in the placentas of L-NAME-induced PE rats [42]. Correspondingly, FABP4 DNA methylation levels were significantly reduced in L-NAME-treated trophoblast cells as well as in the placentas of preeclamptic patients [42]. Elevated FABP4 expression in L-NAME-treated trophoblasts led to accumulation of lipids and release of pro-inflammatory cytokines [42]. A separate study also reported significantly higher FABP4 mRNA and protein levels in the placentas of PE women [240]. It was found that inhibition of FABP4 in two trophoblast cell lines (Swan 71 and JAr) inhibited the proliferation, migration, and invasion of trophoblasts, indicating a key role for FABP4 in placental development [240]. Another study observed a significant increase in FABP4 levels in placentas from mild and severe PE patients, showing a correlation with elevated FABP4 and reduced high density lipoprotein in the sera [241]. Multiple studies have found higher circulating levels of FABP4, from as early as the first prenatal visit [242] to 8–13 and 24–48 weeks [243], 14 and 26 weeks [244], and the third trimester [231,232]. An in vitro study in BeWo trophoblast cells exposed to hypoxia validated two HREs in in the promoter of FABP4 [245]. This suggests that, in addition to the miR-148/152 family inhibiting DNMT1 and reducing methylation of FABP4, other factors may contribute to the elevated FABP4 levels seen in PE patients (Figure 3).

MiRNAs as therapeutic targets

The number of miRNA-based therapeutics in clinical trials has steadily been increasing over the past decade, with phase I and II trials currently underway [246]. While the majority of miRNA therapeutics under development are for the treatment of cancer, researchers have been investigating their utility for viral infections and neurological, metabolic, inflammatory, and cardiovascular disorders [247]. Strategies to target dysregulated miRNAs are inhibitors (traditionally anti-miRNA oligonucleotides known as antagomirs that are complementary to the target miRNA) or mimics (primarily chemically synthesized double stranded RNA molecules) [248]. Use of these hydrophilic agents however carries disadvantages in terms of nuclease degradation, off-target binding, and poor cell membrane penetration [249]. In turn, a number of strategies have been introduced to enhance the efficiency and specificity of inhibiting or restoring miRNAs, including locked nucleic acid anti-miRs and miR-sponges and miRNA vectors and small molecules, respectively [248]. Furthermore, novel delivery systems using peptides and lipid nanoparticles have been developed to provide further protection against nucleases, prevent immune attacks, and improve targeted delivery [248]. The unique ability of miRNAs to target multiple genes and in turn specific components of a biological pathway or even entire or multiple biological pathways underlies their potential as therapeutic targets. For example, MGN-9103, an inhibitor of the cardiac specific miR-208a, has shown to prevent pathological cardiac remodeling in a heart-failure rat model, leading to improved cardiac function, overall health, and survival [250]. Microarray analysis revealed 131 genes were significantly differentially expressed in the hearts of treatment mice, of which 31 were identified as predicted gene targets of miR-208a [250]. Of the predicted targets, 28 genes were significantly increased, corresponding with an inhibition of miR-208a permitting an upregulation of otherwise inhibited target genes [250]. Although these findings demonstrate the therapeutic benefit of miRNAs’ pleiotropic nature, off-target effects and unintended toxicity are a key concern among miRNA-based therapeutics. Identifying a suitable miRNA target and developing efficient delivery systems to achieve therapeutically relevant outcomes therefore remain essential and represent major hurdles in developing clinically translatable miRNA-based therapeutics. These challenges are mirrored in research seeking to target altered placental miRNAs in pregnancy disorders.

Given the heterogeneous nature of PE, it is unlikely that a single placental miRNA will present itself as a suitable therapeutic target. Studies continue to investigate the utility of stratifying preeclamptic patients into distinct subtypes based on biomarkers, genetics, pathology, and/or clinical phenotypes; however, patients often present with overlapping elements and intermediate phenotypes [180,251–253]. In turn, the International Society for the Study of Hypertension in Pregnancy guidelines recommend classifying PE as with or without severe features or as superimposed (when pre-eclampsia develops in women with pre-existing chronic hypertension) and restricting the use of ‘mild’, ‘severe’, ‘EO’, and ‘LO’ to research [3]. These classifications highlight the diverse disease presentation seen among PE patients. Furthermore, microarray and next-generation sequencing studies in the blood [254] and placentas [255–257] of patients with different PE subtypes demonstrate not only common but also distinct gene expression profiles. Genetic heterogeneity among PE subtypes is similarly evident in terms of placental miRNAs [19,70,183,255,258,259] and partially explains inconsistencies in their reported direction of expression as previously discussed. However, it remains to be seen whether a differentially expressed placental miRNA may be restricted to specific subtype and therefore represent a precision medicine approach to targeting miRNAs in PE. In support of this approach are the increasing number of studies that show altered miRNAs in the blood early in gestation in preeclamptic patients correspond with differentially expressed miRNAs in preeclamptic placentas at term [260–263] and can therefore act as non-invasive biomarkers, with a recent study demonstrating their utility as biomarkers for PE subtypes [21]. A dysregulated blood-based miRNA in a subset of PE patients corresponding with altered expression in the placenta and therefore representing a therapeutic target conceptually illustrates an ideal scenario. However, altered miRNA expression profiles in PE subtypes both in maternal blood and the placenta still require validation in larger cohorts and replication in independent cohorts, presenting a challenge given the difficulty of recruiting pregnant patients for clinical samples. Hence, a suitable miRNA target for the treatment of preeclampsia, likely restricted to a subset of patients, remains to be identified.

In the previously mentioned study by Yan et al. [41], rats administered L-NAME showed significantly higher SBP and urinary protein levels compared with controls, providing evidence of a PE phenotype. Treatment rats went on to receive an intra-placental injection of Cy3-labeled agomiR-126, a miR-126 mimic [41]. This led to a 4.2-fold increase in miR-126 expression in treatment rats compared with non-treated PE rats [41]. In the placentas of the treatment rats, patches of miR-126 were detected by fluorescence microscopy, which were notably absent from PE and control rats [41]. These findings highlight the potential of intraplacental delivery of miRNA mimics for targeting the placenta, but investigation of miR-126 expression across other tissues would be required to confirm placenta-specific delivery. MiR-126 treated rats had significantly higher pup and placenta weights, enhanced microvessel density, and greater proportion of live pups [41]. Although there was a reduction in SBP by 15% in miR-126 treated rat compared with PE rats, this was not significant, and urinary protein levels were not reported. These findings support a key role for miR-126 in contributing to the clinical manifestations of PE even though clinically relevant therapeutic outcomes, in terms of blood pressure and urinary protein levels, were not achieved. Based on clinical studies reporting both up- and downregulation of miR-126, it is unlikely that miR-126 represents a suitable therapeutic target for all PE patients. This further supports the concept that altered miRNAs may underlie unique signatures of PE subtypes and identifying these should be the focus of future clinical studies. Accordingly, it may be more valuable to assess the therapeutic effect of targeting miRNAs in animal models of specific PE subtypes (e.g. EO, LO, mild, severe, and superimposed). Finally, with cell-dependent expression of miR-126 potentially contributing to inconsistencies in its direction of expression, targeting at the cellular versus tissue level may be essential for achieving therapeutically relevant outcomes. Both viral [264] and non-viral [265] delivery systems seeking to attain cell-specific targeting of miRNAs are under development but remain unexplored in the placenta in vivo, a potential novel avenue for research.

Currently under investigation is tissue-level targeting of placental miRNAs, which in itself represents a challenge. A recent study by Beards et al. [266] examined the feasibility of placental homing peptide-miRNA inhibitor conjugates as a therapeutic strategy for pregnancy disorders. A non-targeting miRNA inhibitor was administered to pregnant C57/BL6J mice intravenously to demonstrate proof-of-concept and assess safety parameters [266]. The inhibitor was detected primarily in the junctional zone, with lower levels evident in the labyrinth and decidua, and none was detected in vehicle control mice [266]. The miRNA inhibitor was not seen in any fetal organs examined but was detected in maternal tissue, namely the heart, liver, kidney, and uterus [266]. The study noted the importance of these findings, indicating systemic delivery of a miRNA inhibitor may lead to off-target effects. No significant difference in median fetal and placental weights, fetal–placental weight ratio, litter size, or number of resorptions was observed though, suggesting the miRNA inhibitor had no serious adverse effects in pregnancy [266]. In the second part of the study, three sequences, namely a scrambled miRNA inhibitor, a miR-145 inhibitor, and a miR-675 inhibitor were conjugated to the peptide CCGKRK and injected intravenously into pregnant mice [266]. These miRNAs were selected since miR-145 and miR-675 have shown to regulate placental growth and function [267–270] and found to be dysregulated in the placenta of pregnancies complicated by PE and intra-uterine growth restriction [270,271]. Inhibition of miR-675 in treatment mice led to a significant reduction in placental miRNA expression and significant elevation in median placental weight compared with control mice [266]. Inhibition of miR-145 did not induce a significant change in placental miRNA expression and median placental weight [266]. This may have arisen due to normalization of miR-145 expression levels, highlighting the issue of targeting miRNAs for a therapeutically relevant period of time. Even though pregnancy has a defined timespan, modulating miRNAs for a sufficient period to achieve a therapeutic benefit is another aspect that must be considered. It should be noted though that both miRNA-inhibitors did cause a significant increase in median fetal weight, and there was no change in litter size or fetal resorptions, indicating the inhibitors were well-tolerated in pregnant mice [266]. While validation of placenta-specific targeting was not examined in the study, the group had previously evaluated the placental homing ability of the CGKRK peptide [272]. The 5[6]-carboxyfluorescein labeled peptide was not detected in the heart, brain, liver, spleen, or lungs, but was found in the kidney [272]. In the placenta, the peptide was detected in decidual spiral arteries and the labyrinth, specifically in the endothelium of unremodeled vessels and endovascular trophoblasts of remodeled vessels, while none was found in the junctional zone [272]. Collectively, these studies demonstrate the potential to target specific cellular compartments of the placenta but also highlight the difficulty of achieving tissue-specific delivery. While cell-specific targeting may represent an ultimate goal, efforts to achieve placental-specific targeting should not be dismissed, particularly given the limited number of in vivo studies examining placental miRNA targeting. Alongside the development of novel delivery systems targeting placental miRNAs, a growing understanding of the pathological role of placental miRNAs in PE underlies their emerging potential as therapeutic targets and as a new form of treatment for PE.

Conclusion

Animal model studies offer essential insight into the molecular and functional mechanisms underlying PE as they permit investigations not possible in pregnant women. Three studies utilizing rodent models of PE explored the role of placental miRNAs, miR-210, miR-126, and miR-148/152 respectively, by examining expression of the miRNAs, their regulators, and gene targets. A comparison of these findings with evidence from clinical studies, other PE animal models, and in vitro studies have allowed us to present a comprehensive evaluation of the interaction of genetic components and pathological processes in the placenta that underlie PE as well as evaluate their suitability as therapeutic targets.

Inconsistencies in the direction of expression of miR-210, miR-126, and miR-148/152 across clinical studies highlight the genetic heterogeneity of PE. It is therefore unlikely that a single placental miRNA may represent a suitable target for all PE patients. Future studies should focus on elucidating altered blood-based and placental miRNA expression profiles in PE patient subtypes or identifying an altered placental miRNA characteristic of a subset of patients as this will permit undertaking a precision medicine approach to targeting potential therapeutic miRNAs. Investigations in animal models of PE may in turn benefit from utilizing specific PE subtype models to elucidate the role of placental miRNAs. Finally, establishing methods for targeting placental miRNAs as well as specific placental cell types remain cornerstone experiments before placental miRNAs may serve as therapeutic targets for a new form of treatment for PE.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by funding from the British Heart Foundation Centre of Excellence award [grant number RE/13/5/30177].

Abbreviations

     
  • Ang

    Angiotensin

  •  
  • BPA

    bisphenol A

  •  
  • CVD

    cardiovascular disease

  •  
  • DNMT1

    DNA-methyltransferase 1

  •  
  • EC

    endothelial cell

  •  
  • EPC

    endothelial progenitor cell

  •  
  • ERK

    extracellular signal–regulated kinase

  •  
  • FABP4

    fatty acid-binding protein 4

  •  
  • GATA3

    GATA binding protein 3

  •  
  • HDL

    high density lipoprotein

  •  
  • HIF-1

    hypoxia-inducible factor 1

  •  
  • HLA-G

    human leukocyte antigen-G

  •  
  • HRE

    hypoxia response element

  •  
  • HUVECs

    human umbilical vein endothelial cells

  •  
  • IL

    interleukin

  •  
  • KO

    knockout

  •  
  • L-NAME

    N(gamma)-nitro-L-arginine methyl ester

  •  
  • LPS

    lipopolysaccharide

  •  
  • mRNA

    messenger RNA

  •  
  • miRNA

    microRNA

  •  
  • MSC

    mesenchymal stem cell

  •  
  • NF-κB

    nuclear factor-κB

  •  
  • pAkt

    phosphorylated Akt

  •  
  • PE

    preeclampsia

  •  
  • PI3K

    phosphatidylinositol 3-kinase

  •  
  • PKB

    protein kinase B

  •  
  • P-PIC

    poly I:C

  •  
  • SBP

    systolic blood pressure

  •  
  • sEng

    soluble endoglin

  •  
  • sFlt-1

    soluble vascular endothelial growth factor receptor-1

  •  
  • SGA

    small for gestational age

  •  
  • SHRSP

    stroke-prone spontaneously hypertensive

  •  
  • SPRED1

    sprouty related EVH1 domain containing 1

  •  
  • STAT6

    signal transducer and activator of transcription 6

  •  
  • Th1

    T-helper type 1

  •  
  • Th2

    T-helper type 2

  •  
  • TLR3

    toll-like receptor 3

  •  
  • TNF-α

    tumour necrosis factor α

  •  
  • VEGF

    vascular endothelial growth factor

  •  
  • WT

    wild type

References

References
1.
Abalos
E.
,
Cuesta
C.
,
Grosso
A.L.
,
Chou
D.
and
Say
L.
(
2013
)
Global and regional estimates of preeclampsia and eclampsia: a systematic review
.
Eur. J. Obstet. Gynecol. Reprod. Biol.
170
,
1
7
[PubMed]
2.
Duley
L.
(
2009
)
The global impact of pre-eclampsia and eclampsia
.
Semin. Perinatol.
33
,
130
137
[PubMed]
3.
Brown
M.A.
,
Magee
L.A.
,
Kenny
L.C.
,
Karumanchi
S.A.
,
McCarthy
F.P.
,
Saito
S.
et al.
(
2018
)
Hypertensive Disorders of Pregnancy: ISSHP Classification, Diagnosis, and Management Recommendations for International Practice
.
Hypertension (Dallas, Tex: 1979)
72
,
24
43
[PubMed]
4.
Cnattingius
S.
,
Reilly
M.
,
Pawitan
Y.
and
Lichtenstein
P.
(
2004
)
Maternal and fetal genetic factors account for most of familial aggregation of preeclampsia: a population-based Swedish cohort study
.
Am. J. Med. Genet. Part A
130a
,
365
371
[PubMed]
5.
Salonen Ros
H.
,
Lichtenstein
P.
,
Lipworth
L.
and
Cnattingius
S.
(
2000
)
Genetic effects on the liability of developing pre-eclampsia and gestational hypertension
.
Am. J. Med. Genet.
91
,
256
260
[PubMed]
6.
Brew
O.
,
Sullivan
M.H.
and
Woodman
A.
(
2016
)
Comparison of Normal and Pre-Eclamptic Placental Gene Expression: A Systematic Review with Meta-Analysis
.
PLoS ONE
11
,
e0161504
[PubMed]
7.
Kleinrouweler
C.E.
,
van Uitert
M.
,
Moerland
P.D.
,
Ris-Stalpers
C.
,
van der Post
J.A.
and
Afink
G.B.
(
2013
)
Differentially expressed genes in the pre-eclamptic placenta: a systematic review and meta-analysis
.
PLoS ONE
8
,
e68991
[PubMed]
8.
Sheikh
A.M.
,
Small
H.Y.
,
Currie
G.
and
Delles
C.
(
2016
)
Systematic Review of Micro-RNA Expression in Pre-Eclampsia Identifies a Number of Common Pathways Associated with the Disease
.
PLoS ONE
11
,
e0160808
[PubMed]
9.
O'Brien
J.
,
Hayder
H.
,
Zayed
Y.
and
Peng
C.
(
2018
)
Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation
.
Front. Endocrinol.
9
,
402
[PubMed]
10.
Lewis
B.P.
,
Burge
C.B.
and
Bartel
D.P.
(
2005
)
Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets
.
Cell
120
,
15
20
[PubMed]
11.
Friedman
R.C.
,
Farh
K.K.
,
Burge
C.B.
and
Bartel
D.P.
(
2009
)
Most mammalian mRNAs are conserved targets of microRNAs
.
Genome Res.
19
,
92
105
[PubMed]
12.
Li
S.C.
,
Chan
W.C.
,
Hu
L.Y.
,
Lai
C.H.
,
Hsu
C.N.
and
Lin
W.C.
(
2010
)
Identification of homologous microRNAs in 56 animal genomes
.
Genomics
96
,
1
9
[PubMed]
13.
Cheloufi
S.
,
Dos Santos
C.O.
,
Chong
M.M.
and
Hannon
G.J.
(
2010
)
A dicer-independent miRNA biogenesis pathway that requires Ago catalysis
.
Nature
465
,
584
589
[PubMed]
14.
Forbes
K.
,
Farrokhnia
F.
,
Aplin
J.D.
and
Westwood
M.
(
2012
)
Dicer-dependent miRNAs provide an endogenous restraint on cytotrophoblast proliferation
.
Placenta
33
,
581
585
[PubMed]
15.
Chen
D.B.
and
Wang
W.
(
2013
)
Human placental microRNAs and preeclampsia
.
Biol. Reprod.
88
,
130
[PubMed]
16.
Malnou
E.C.
,
Umlauf
D.
,
Mouysset
M.
and
Cavaille
J.
(
2018
)
Imprinted MicroRNA Gene Clusters in the Evolution, Development, and Functions of Mammalian Placenta
.
Front. Genet.
9
,
706
[PubMed]
17.
Inoue
K.
,
Hirose
M.
,
Inoue
H.
,
Hatanaka
Y.
,
Honda
A.
,
Hasegawa
A.
et al.
(
2017
)
The Rodent-Specific MicroRNA Cluster within the Sfmbt2 Gene Is Imprinted and Essential for Placental Development
.
Cell Rep.
19
,
949
956
[PubMed]
18.
Hromadnikova
I.
,
Kotlabova
K.
,
Ondrackova
M.
,
Pirkova
P.
,
Kestlerova
A.
,
Novotna
V.
et al.
(
2015
)
Expression profile of C19MC microRNAs in placental tissue in pregnancy-related complications
.
DNA Cell Biol.
34
,
437
457
[PubMed]
19.
Zhu
X.M.
,
Han
T.
,
Sargent
I.L.
,
Yin
G.W.
and
Yao
Y.Q.
(
2009
)
Differential expression profile of microRNAs in human placentas from preeclamptic pregnancies vs normal pregnancies
.
Am. J. Obstet. Gynecol.
200
,
661.e1
667.e1
20.
Hromadnikova
I.
,
Kotlabova
K.
,
Ivankova
K.
and
Krofta
L.
(
2017
)
First trimester screening of circulating C19MC microRNAs and the evaluation of their potential to predict the onset of preeclampsia and IUGR
.
PLoS ONE
12
,
e0171756
[PubMed]
21.
Timofeeva
A.V.
,
Gusar
V.A.
,
Kan
N.E.
,
Prozorovskaya
K.N.
,
Karapetyan
A.O.
,
Bayev
O.R.
et al.
(
2018
)
Identification of potential early biomarkers of preeclampsia
.
Placenta
61
,
61
71
[PubMed]
22.
Jiang
L.
,
Long
A.
,
Tan
L.
,
Hong
M.
,
Wu
J.
,
Cai
L.
et al.
(
2017
)
Elevated microRNA-520g in pre-eclampsia inhibits migration and invasion of trophoblasts
.
Placenta
51
,
70
75
[PubMed]
23.
Zhang
M.
,
Muralimanoharan
S.
,
Wortman
A.C.
and
Mendelson
C.R.
(
2016
)
Primate-specific miR-515 family members inhibit key genes in human trophoblast differentiation and are upregulated in preeclampsia
.
PNAS
113
,
E7069
E7076
[PubMed]
24.
Lalevée
S.
,
Lapaire
O.
and
Bühler
M.
,
miR455 is linked to hypoxia signaling and is deregulated in preeclampsia
.
Cell Death Dis.
2014
,
e1408
25.
Jiang
F.
,
Li
J.
,
Wu
G.
,
Miao
Z.
,
Lu
L.
,
Ren
G.
et al.
(
2015
)
Upregulation of microRNA335 and microRNA584 contributes to the pathogenesis of severe preeclampsia through downregulation of endothelial nitric oxide synthase
.
Mol. Med. Rep.
12
,
5383
5390
[PubMed]
26.
Zhou
X.
,
Li
Q.
,
Xu
J.
,
Zhang
X.
,
Zhang
H.
,
Xiang
Y.
et al.
(
2016
)
The aberrantly expressed miR-193b-3p contributes to preeclampsia through regulating transforming growth factor-beta signaling
.
Sci. Rep.
6
,
19910
[PubMed]
27.
Furukawa
S.
,
Kuroda
Y.
and
Sugiyama
A.
(
2014
)
A comparison of the histological structure of the placenta in experimental animals
.
J. Toxicologic Pathol.
27
,
11
18
[PubMed]
28.
Soncin
F.
,
Khater
M.
,
To
C.
,
Pizzo
D.
,
Farah
O.
,
Wakeland
A.
et al.
(
2018
)
Comparative analysis of mouse and human placentae across gestation reveals species-specific regulators of placental development
.
Development
145
,
29.
Conrad
K.P.
(
2004
)
Mechanisms of renal vasodilation and hyperfiltration during pregnancy
.
J. Soc. Gynecol. Investig.
11
,
438
448
[PubMed]
30.
Paller
M.S.
(
1984
)
Mechanism of decreased pressor responsiveness to ANG II, NE, and vasopressin in pregnant rats
.
Am. J. Physiol.
247
,
H100
H108
[PubMed]
31.
Meyer
M.C.
,
Brayden
J.E.
and
McLaughlin
M.K.
(
1993
)
Characteristics of vascular smooth muscle in the maternal resistance circulation during pregnancy in the rat
.
Am. J. Obstet. Gynecol.
169
,
1510
1516
[PubMed]
32.
Wong
A.Y.
,
Kulandavelu
S.
,
Whiteley
K.J.
,
Qu
D.
,
Langille
B.L.
and
Adamson
S.L.
(
2002
)
Maternal cardiovascular changes during pregnancy and postpartum in mice
.
Am. J. Physiol. Heart Circulat. Physiol.
282
,
H918
H925
[PubMed]
33.
McCarthy
F.P.
,
Kingdom
J.C.
,
Kenny
L.C.
and
Walsh
S.K.
(
2011
)
Animal models of preeclampsia; uses and limitations
.
Placenta
32
,
413
419
[PubMed]
34.
Hennessy
A.
,
Gillin
A.G.
,
Painter
D.M.
,
Kirwan
P.J.
,
Thompson
J.F.
and
Horvath
J.S.
(
1997
)
Evidence for Preeclampsia in a Baboon Pregnancy with Twins
.
Hypertens. Pregnancy
16
,
223
228
35.
Krugner-Higby
L.
,
Luck
M.
,
Hartley
D.
,
Crispen
H.M.
,
Lubach
G.R.
and
Coe
C.L.
(
2009
)
High-risk pregnancy in rhesus monkeys (Macaca mulatta): a case of ectopic, abdominal pregnancy with birth of a live, term infant, and a case of gestational diabetes complicated by pre-eclampsia
.
J. Med. Primatol.
38
,
252
256
[PubMed]
36.
Palmer
A.E.
,
London
W.T.
,
Sly
D.L.
and
Rice
J.M.
(
1979
)
Spontaneous preeclamptic toxemia of pregnancy in the patas monkey (Erythrocebus patas)
.
Lab. Anim. Sci.
29
,
102
106
[PubMed]
37.
Thornton
J.G.
and
Onwude
J.L.
(
1992
)
Convulsions in pregnancy in related gorillas
.
Am. J. Obstet. Gynecol.
167
,
240
241
[PubMed]
38.
Pijnenborg
R.
,
Vercruysse
L.
and
Carter
A.M.
(
2011
)
Deep trophoblast invasion and spiral artery remodelling in the placental bed of the chimpanzee
.
Placenta
32
,
400
408
[PubMed]
39.
Silva
J.F.
and
Serakides
R.
(
2016
)
Intrauterine trophoblast migration: A comparative view of humans and rodents
.
Cell Adh. Migr.
10
,
88
110
40.
Kopriva
S.E.
,
Chiasson
V.L.
,
Mitchell
B.M.
and
Chatterjee
P.
(
2013
)
TLR3-induced placental miR-210 down-regulates the STAT6/interleukin-4 pathway
.
PLoS ONE
8
,
e67760
[PubMed]
41.
Yan
T.
,
Cui
K.
,
Huang
X.
,
Ding
S.
,
Zheng
Y.
,
Luo
Q.
et al.
(
2014
)
Assessment of therapeutic efficacy of miR-126 with contrast-enhanced ultrasound in preeclampsia rats
.
Placenta
35
,
23
29
[PubMed]
42.
Yang
A.
,
Zhang
H.
,
Sun
Y.
,
Wang
Y.
,
Yang
X.
,
Yang
X.
et al.
(
2016
)
Modulation of FABP4 hypomethylation by DNMT1 and its inverse interaction with miR-148a/152 in the placenta of preeclamptic rats and HTR-8 cells
.
Placenta
46
,
49
62
[PubMed]
43.
Bavelloni
A.
,
Ramazzotti
G.
,
Poli
A.
,
Piazzi
M.
,
Focaccia
E.
,
Blalock
W.
et al.
(
2017
)
MiRNA-210: A Current Overview
.
Anticancer Res.
12
,
6511
6521
44.
Chan
Y.C.
,
Banerjee
J.
,
Choi
S.Y.
and
Sen
C.K.
(
2012
)
miR-210: the master hypoxamir
.
Microcirculation
3
,
215
223
45.
Chan
S.Y.
and
Loscalzo
J.
(
2010
)
MicroRNA-210: a unique and pleiotropic hypoxamir
.
Cell Cycle (Georgetown, Tex)
9
,
1072
1083
[PubMed]
46.
Devlin
C.
,
Greco
S.
,
Martelli
F.
and
Ivan
M.
(
2011
)
miR-210: More than a silent player in hypoxia
.
IUBMB Life
2
,
94
100
47.
Biswas
S.
,
Roy
S.
,
Banerjee
J.
,
Hussain
S.R.
,
Khanna
S.
,
Meenakshisundaram
G.
et al.
(
2010
)
Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds
.
PNAS
107
,
6976
6981
[PubMed]
48.
Endo
K.
,
Naito
Y.
,
Ji
X.
,
Nakanishi
M.
,
Noguchi
T.
,
Goto
Y.
et al.
(
2013
)
MicroRNA 210 as a biomarker for congestive heart failure
.
Biol. Pharm. Bull.
36
,
48
54
49.
Li
T.
,
Cao
H.
,
Zhuang
J.
,
Wan
J.
,
Guan
M.
,
Yu
B.
et al.
(
2011
)
Identification of miR-130a, miR-27b and miR-210 as serum biomarkers for atherosclerosis obliterans
.
Clin. Chim. Acta
412
,
66
70
[PubMed]
50.
Lou
Y.L.
,
Guo
F.
,
Liu
F.
,
Gao
F.L.
,
Zhang
P.Q.
,
Niu
X.
et al.
(
2012
)
miR-210 activates notch signaling pathway in angiogenesis induced by cerebral ischemia
.
Mol. Cell. Biochem.
370
,
45
51
[PubMed]
51.
Kim
J.H.
,
Park
S.G.
,
Song
S.Y.
,
Kim
J.K.
and
Sung
J.H.
,
Reactive oxygen species-responsive miR-210 regulates proliferation and migration of adipose-derived stem cells via PTPN2
.
Cell Death Dis.
2013
,
e588
52.
Mok
Y.
,
Schwierzeck
V.
,
Thomas
D.C.
,
Vigorito
E.
,
Rayner
T.F.
,
Jarvis
L.B.
et al.
(
2013
)
MiR-210 is induced by Oct-2, regulates B cells, and inhibits autoantibody production
.
J. Immunol.
6
,
3037
3048
53.
Chatterjee
P.
,
Chiasson
V.L.
,
Kopriva
S.E.
,
Young
K.J.
,
Chatterjee
V.
,
Jones
K.A.
et al.
(
2011
)
Interleukin 10 deficiency exacerbates toll-like receptor 3-induced preeclampsia-like symptoms in mice
.
Hypertension (Dallas, Tex: 1979)
58
,
489
496
[PubMed]
54.
Krawczynski
K.
,
Mishima
T.
,
Huang
X.
and
Sadovskya
Y.
(
2016
)
Intact feto-placental growth in microRNA-210 deficient mice
.
Placenta
113
115
[PubMed]
55.
Hu
X.Q.
,
Dasgupta
C.
,
Xiao
D.
,
Huang
X.
,
Yang
S.
and
Zhang
L.
(
2017
)
MicroRNA-210 Targets Ten-Eleven Translocation Methylcytosine Dioxygenase 1 and Suppresses Pregnancy-Mediated Adaptation of Large Conductance Ca2+-Activated K+ Channel Expression and Function in Ovine Uterine Arteries
.
Hypertension (Dallas, Tex: 1979)
70
,
56.
Zamudio
S.
(
2007
)
High-altitude hypoxia and preeclampsia
.
Front. Biosci.
2967
2977
[PubMed]
57.
Soleymanlou
N.
,
Jurisica
I.
,
Nevo
O.
,
Ietta
F.
,
Zhang
X.
,
Zamudio
S.
et al.
(
2005
)
Molecular evidence of placental hypoxia in preeclampsia
.
J. Clin. Endocrinol. Metab.
7
,
4299
4308
58.
Palmer
S.K.
,
Moore
L.G.
,
Young
D.
,
Cregger
B.
,
Berman
J.C.
and
Zamudio
S.
(
1999
)
Altered blood pressure course during normal pregnancy and increased preeclampsia at high altitude (3100 meters) in Colorado
.
Am. J. Obstet. Gynecol.
5
,
1161
1168
59.
Keyes
L.E.
,
Armaza
J.F.
,
Niermeyer
S.
,
Vargas
E.
,
Young
D.A.
and
Moore
L.G.
(
2003
)
Intrauterine growth restriction, preeclampsia, and intrauterine mortality at high altitude in Bolivia
.
Pediatr. Res.
1
,
20
25
60.
Moore
L.G.
,
Hershey
D.W.
,
Jahnigen
D.
and
Bowes
W.J.
(
1982
)
The incidence of pregnancy-induced hypertension is increased among Colorado residents at high altitude
.
Am. J. Obstet. Gynecol.
4
,
423
429
61.
Colleoni
F.
,
Padmanabhan
N.
,
Yung
H.W.
,
Watson
E.D.
,
Cetin
I.
,
Tissot van Patot
M.C.
et al.
(
2013
)
Suppression of mitochondrial electron transport chain function in the hypoxic human placenta: a role for miRNA-210 and protein synthesis inhibition
.
PLoS ONE
8
,
e55194
[PubMed]
62.
Ura
B.
,
Feriotto
G.
,
Monasta
L.
,
Bilel
S.
,
Zweyer
M.
and
Celeghini
C.
(
2014
)
Potential role of circulating microRNAs as early markers of preeclampsia
.
Taiwan J. Obstet Gynecol.
2
,
232
234
63.
Anton
L.
,
Olarerin-George
A.O.
,
Schwartz
N.
,
Srinivas
S.
,
Bastek
J.
,
Hogenesch
J.B.
et al.
(
2013
)
miR-210 inhibits trophoblast invasion and is a serum biomarker for preeclampsia
.
Am. J. Pathol.
183
,
1437
1445
[PubMed]
64.
Enquobahrie
D.A.
,
Abetew
D.F.
,
Sorensen
T.K.
,
Willoughby
D.
,
Chidambaram
K.
and
Williams
M.A.
(
2011
)
Placental microRNA expression in pregnancies complicated by preeclampsia
.
Am. J. Obstet. Gynecol.
2
,
e12
e21
65.
Ishibashi
O.
,
Ohkuchi
A.
,
Ali
M.M.
,
Kurashina
R.
,
Luo
S.S.
,
Ishikawa
T.
et al.
(
2012
)
Hydroxysteroid (17-beta) dehydrogenase 1 is dysregulated by miR-210 and miR-518c that are aberrantly expressed in preeclamptic placentas: a novel marker for predicting preeclampsia
.
Hypertension (Dallas, Tex: 1979)
59
,
265
273
[PubMed]
66.
Muralimanoharan
S.
,
Maloyan
A.
,
Mele
J.
,
Guo
C.
,
Myatt
L.G.
and
Myatt
L.
(
2012
)
MIR-210 modulates mitochondrial respiration in placenta with preeclampsia
.
Placenta
33
,
816
823
[PubMed]
67.
Zhang
Y.
,
Fei
M.
,
Xue
G.
,
Zhou
Q.
,
Jia
Y.
,
Li
L.
et al.
(
2012
)
Elevated levels of hypoxia-inducible microRNA-210 in pre-eclampsia: new insights into molecular mechanisms for the disease
.
J. Cell. Mol. Med.
16
,
249
259
[PubMed]
68.
Betoni
J.S.
,
Derr
K.
,
Pahl
M.C.
,
Rogers
L.
,
Muller
C.L.
,
Packard
R.E.
et al.
(
2013
)
MicroRNA analysis in placentas from patients with preeclampsia: comparison of new and published results
.
Hypertens. Pregnancy
32
,
321
339
[PubMed]
69.
Luo
R.
,
Shao
X.
,
Xu
P.
,
Liu
Y.
,
Wang
Y.
,
Zhao
Y.
et al.
(
2014
)
MicroRNA-210 contributes to preeclampsia by downregulating potassium channel modulatory factor 1
.
Hypertension (Dallas, Tex: 1979)
64
,
839
845
[PubMed]
70.
Weedon-Fekjær
M.S.
,
Sheng
Y.
,
Sugulle
M.
,
Johnsen
G.M.
,
Herse
F.
,
Redman
C.W.
et al.
(
2014
)
Placental miR-1301 is dysregulated in early-onset preeclampsia and inversely correlated with maternal circulating leptin
.
Placenta
9
,
709
717
71.
Xu
P.
,
Zhao
Y.
,
Liu
M.
,
Wang
Y.
,
Wang
H.
,
Li
Y.X.
et al.
(
2014
)
Variations of microRNAs in human placentas and plasma from preeclamptic pregnancy
.
Hypertension (Dallas, Tex: 1979)
63
,
1276
1284
[PubMed]
72.
Zhang
C.
,
Li
Q.
,
Ren
N.
,
Li
C.
,
Wang
X.
,
Xie
M.
et al.
(
2015
)
Placental miR-106a ∼ 363 cluster is dysregulated in preeclamptic placenta
.
Placenta
36
,
250
252
[PubMed]
73.
Vashukova
E.S.
,
Glotov
A.S.
,
Fedotov
P.V.
,
Efimova
O.A.
,
Pakin
V.S.
,
Mozgovaya
E.V.
et al.
(
2016
)
Placental microRNA expression in pregnancies complicated by superimposed preeclampsia on chronic hypertension
.
Mol. Med. Rep.
14
,
22
32
[PubMed]
74.
Adel
S.
,
Mansour
A.
,
Louka
M.
,
Matboli
M.
,
Elmekkawi
S.F.
and
Swelam
N.
(
2017
)
Evaluation of MicroRNA-210 and Protein tyrosine phosphatase, non-receptor type 2 in Pre-eclampsia
.
Gene
596
,
105
109
[PubMed]
75.
Gan
L.
,
Liu
Z.
,
Wei
M.
,
Chen
Y.
,
Yang
X.
,
Chen
L.
et al.
(
2017
)
MiR-210 and miR-155 as potential diagnostic markers for pre-eclampsia pregnancies
.
Medicine (Baltimore)
28
,
e7515
76.
Jairajpuri
D.S.
,
Malalla
Z.H.
,
Mahmood
N.
and
Almawi
W.Y.
(
2017
)
Circulating microRNA expression as predictor of preeclampsia and its severity
.
Gene
627
,
543
548
[PubMed]
77.
Chen
J.
,
Zhao
L.
,
Wang
D.
,
Xu
Y.
,
Gao
H.
,
Tan
W.
et al.
(
2019
)
Contribution of regulatory T cells to immune tolerance and association of microRNA210 and Foxp3 in preeclampsia
.
Mol. Med. Rep.
19
,
1150
1158
[PubMed]
78.
Nejad
R.M.A.
,
Saeidi
K.
,
Gharbi
S.
,
Salari
Z.
and
Saleh-Gohari
N.
(
2019
)
Quantification of circulating miR-517c-3p and miR-210-3p levels in preeclampsia
.
Pregnancy Hypertens.
16
,
75
78
[PubMed]
79.
Wang
R.
,
Liu
W.
,
Liu
X.
,
Liu
X.
,
Tao
H.
,
Wu
D.
et al.
(
2019
)
MicroRNA-210 regulates human trophoblast cell line HTR-8/SVneo function by attenuating Notch1 expression: Implications for the role of microRNA-210 in pre-eclampsia
.
Mol. Reprod. Dev.
86
,
896
907
[PubMed]
80.
Wyatt
S.M.
,
Kraus
F.T.
,
Roh
C.R.
,
Elchalal
U.
,
Nelson
D.M.
and
Sadovsky
Y.
(
2005
)
The correlation between sampling site and gene expression in the term human placenta
.
Placenta
26
,
372
379
[PubMed]
81.
Sood
R.
,
Zehnder
J.L.
,
Druzin
M.L.
and
Brown
P.O.
(
2006
)
Gene expression patterns in human placenta
.
PNAS
103
,
5478
5483
[PubMed]
82.
Gormley
M.
,
Ona
K.
,
Kapidzic
M.
,
Garrido-Gomez
T.
,
Zdravkovic
T.
and
Fisher
S.J.
(
2017
)
Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations
.
Am. J. Obstet. Gynecol.
217
,
200.e1
200.e17
83.
Liu
W.
,
Shen
S.M.
,
Zhao
X.Y.
and
Chen
G.Q.
(
2012
)
Targeted genes and interacting proteins of hypoxia inducible factor-1
.
Int. J. Biochem. Mol. Biol.
3
,
165
178
[PubMed]
84.
Cowden Dahl
K.D.
,
Fryer
B.H.
,
Mack
F.A.
,
Compernolle
V.
,
Maltepe
E.
,
Adelman
D.M.
et al.
(
2005
)
Hypoxia-Inducible Factors 1α and 2α Regulate Trophoblast Differentiation
.
Mol. Cell. Biol.
25
,
10479
10491
[PubMed]
85.
Tal
R.
,
Shaish
A.
,
Barshack
I.
,
Polak-Charcon
S.
,
Afek
A.
,
Volkov
A.
et al.
(
2010
)
Effects of hypoxia-inducible factor-1alpha overexpression in pregnant mice: possible implications for preeclampsia and intrauterine growth restriction
.
Am. J. Pathol.
6
,
2950
2962
86.
Nevo
O.
,
Soleymanlou
N.
,
Wu
Y.
,
Xu
J.
,
Kingdom
J.
,
Many
A.
et al.
(
2006
)
Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1
.
Am. J. Physiol. Regulat. Integr. Comp. Physiol.
291
,
R1085
R1093
[PubMed]
87.
Caniggia
I.
,
Mostachfi
H.
,
Winter
J.
,
Gassmann
M.
,
Lye
S.J.
,
Kuliszewski
M.
et al.
(
2000
)
Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3)
.
J. Clin. Invest.
105
,
577
587
[PubMed]
88.
Sanchez-Elsner
T.
,
Botella
L.M.
,
Velasco
B.
,
Langa
C.
and
Bernabeu
C.
(
2002
)
Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways
.
J. Biol. Chem.
277
,
43799
43808
[PubMed]
89.
Tinsley
J.H.
,
Chiasson
V.L.
,
Mahajan
A.
,
Young
K.J.
and
Mitchell
B.M.
(
2009
)
Toll-like receptor 3 activation during pregnancy elicits preeclampsia-like symptoms in rats
.
Am. J. Hypertens.
12
,
1314
1319
90.
Chatterjee
P.
,
Weaver
L.E.
,
Doersch
K.M.
,
Kopriva
S.E.
,
Chiasson
V.L.
,
Allen
S.J.
et al.
(
2012
)
Placental Toll-like receptor 3 and Toll-like receptor 7/8 activation contributes to preeclampsia in humans and mice
.
PLoS ONE
7
,
e41884
[PubMed]
91.
Chattopadhyay
S.
and
Sen
G.C.
(
2014
)
dsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects
.
J. Interferon Cytokine Res.
34
,
427
436
[PubMed]
92.
Mitchell
W.M.
,
Nicodemus
C.F.
,
Carter
W.A.
,
Horvath
J.C.
and
Strayer
D.R.
(
2014
)
Discordant biological and toxicological species responses to TLR3 activation
.
Am. J. Pathol.
4
,
1062
1072
93.
Nakada
E.
,
Walley
K.R.
,
Nakada
T.
,
Hu
Y.
,
von Dadelszen
P.
and
Boyd
J.H.
(
2009
)
Toll-like receptor-3 stimulation upregulates sFLT-1 production by trophoblast cells
.
Placenta
9
,
774
779
94.
Oeckinghaus
A.
and
Ghosh
S.
(
2009
)
The NF-κB Family of Transcription Factors and Its Regulation
.
Cold Spring Harb. Perspect. Biol.
4
,
a000034
95.
Cindrova-Davies
T.
,
Spasic-Boskovic
O.
,
Jauniaux
E.
,
Charnock-Jones
D.S.
and
Burton
G.J.
(
2007
)
Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins
.
Am. J. Pathol.
170
,
1511
1520
[PubMed]
96.
Huang
X.
,
Ding
L.
,
Bennewith
K.L.
,
Tong
R.T.
,
Welford
S.M.
,
Ang
K.K.
et al.
(
2009
)
Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation
.
Mol. Cell
35
,
856
867
[PubMed]
97.
Fasanaro
P.
,
D'Alessandra
Y.
,
Di Stefano
V.
,
Melchionna
R.
,
Romani
S.
,
Pompilio
G.
et al.
(
2008
)
MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3
.
J. Biol. Chem.
23
,
15878
15883
98.
Li
L.
,
Huang
X.
,
He
Z.
,
Xiong
Y.
and
Fang
Q.
(
2019
)
miRNA-210-3p regulates trophoblast proliferation and invasiveness through fibroblast growth factor 1 in selective intrauterine growth restriction
.
J. Cell. Mol. Med.
23
,
4422
4433
[PubMed]
99.
Luo
R.
,
Wang
Y.
,
Xu
P.
,
Cao
G.
,
Zhao
Y.
,
Shao
X.
et al.
(
2016
)
Hypoxia-inducible miR-210 contributes to preeclampsia via targeting thrombospondin type I domain containing 7A
.
Sci. Rep.
6
,
19588
[PubMed]
100.
Wenzel
K.
,
Rajakumar
A.
,
Haase
H.
,
Geusens
N.
,
Hubner
N.
,
Schulz
H.
et al.
(
2011
)
Angiotensin II type 1 receptor antibodies and increased angiotensin II sensitivity in pregnant rats
.
Hypertension (Dallas, Tex: 1979)
1
,
77
84
101.
Reijnders
D.
,
Liu
C.C.
,
Xu
X.
,
Zhao
A.M.
,
Olson
K.N.
,
Butler
S.D.
et al.
(
2018
)
Celecoxib restores angiogenic factor expression at the maternal-fetal interface in the BPH/5 mouse model of preeclampsia
.
Physiol. Genomics
5
,
385
392
102.
Bobek
G.
,
Surmon
L.
,
Mirabito
K.M.
,
Makris
A.
and
Hennessy
A.
(
2015
)
Placental Regulation of Inflammation and Hypoxia after TNF-α Infusion in Mice
.
Am. J. Reprod. Immunol.
5
,
407
418
103.
Gillis
E.E.
,
Williams
J.M.
,
Garrett
M.R.
,
Mooney
J.N.
and
Sasser
J.M.
(
2015
)
The Dahl salt-sensitive rat is a spontaneous model of superimposed preeclampsia
.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
1
,
R62
R70
104.
Iriyama
T.
,
Wang
W.
,
Parchim
N.F.
,
Song
A.
,
Blackwell
S.C.
,
Sibai
B.M.
et al.
(
2015
)
Hypoxia-independent upregulation of placental hypoxia inducible factor-1α gene expression contributes to the pathogenesis of preeclampsia
.
Hypertension (Dallas, Tex: 1979)
6
,
1307
1315
105.
Yang
H.
,
An
B.S.
,
Choi
K.C.
and
Jeung
E.B.
(
2013
)
Change of genes in calcium transport channels caused by hypoxic stress in the placenta, duodenum, and kidney of pregnant rats
.
Biol. Reprod.
2
,
30
106.
Morgan
H.L.
,
Butler
E.
,
Ritchie
S.
,
Herse
F.
,
Dechend
R.
,
Beattie
E.
et al.
(
2018
)
Modeling Superimposed Preeclampsia Using Ang II (Angiotensin II) Infusion in Pregnant Stroke-Prone Spontaneously Hypertensive Rats
.
Hypertension (Dallas, Tex: 1979)
1
,
208
218
107.
Small
H.Y.
,
Morgan
H.
,
Beattie
E.
,
Griffin
S.
,
Indahl
M.
,
Delles
C.
et al.
(
2016
)
Abnormal uterine artery remodelling in the stroke prone spontaneously hypertensive rat
.
Placenta
34
44
[PubMed]
108.
Caniggia
I.
and
Winter
J.L.
(
2002
)
Adriana and Luisa Castellucci Award lecture 2001. Hypoxia inducible factor-1: oxygen regulation of trophoblast differentiation in normal and pre-eclamptic pregnancies–a review
.
Placenta
S47
S57
[PubMed]
109.
Rajakumar
A.
,
Brandon
H.M.
,
Daftary
A.
,
Ness
R.
and
Conrad
K.P.
(
2004
)
Evidence for the functional activity of hypoxia-inducible transcription factors overexpressed in preeclamptic placentae
.
Placenta
10
,
763
769
110.
Akhilesh
M.
,
Mahalingam
V.
,
Nalliah
S.
,
Ali
R.M.
,
Ganesalingam
M.
and
Haleagrahara
N.
(
2013
)
Hypoxia-inducible factor-1α as a predictive marker in pre-eclampsia
.
Biomed. Rep.
2
,
257
258
111.
Sezer
S.D.
,
Küçük
M.
,
Döger
F.K.
,
Yüksel
H.
,
Odabaşi
A.R.
,
Türkmen
M.K.
et al.
(
2013
)
VEGF, PIGF and HIF-1α in placentas of early- and late-onset pre-eclamptic patients
.
Gynecol. Endocrinol.
8
,
797
800
112.
Park
J.K.
,
Kang
T.G.
,
Kang
M.Y.
,
Park
J.E.
,
Cho
I.A.
,
Shin
J.K.
et al.
(
2014
)
Increased NFAT5 expression stimulates transcription of Hsp70 in preeclamptic placentas
.
Placenta
2
,
109
116
113.
Ali
L.E.
,
Salih
M.M.
,
Elhassan
E.M.
,
Mohmmed
A.A.
and
Adam
I.
(
2018
)
Placental growth factor, vascular endothelial growth factor, and hypoxia-inducible factor-1α in the placentas of women with pre-eclampsia
.
J. Matern. Fetal Neonatal Med.
1
5
[PubMed]
114.
Kurlak
L.O.
,
Williams
P.J.
,
Bulmer
J.N.
,
Broughton Pipkin
F.
and
Mistry
H.D.
(
2015
)
Placental expression of adenosine A(2A) receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: interactions with placental renin-angiotensin system
.
Placenta
5
,
611
613
115.
Su
D.M.
(
2016
)
Correlation of STAT4 and STAT6 expression levels in preeclampsia placenta with sFlt-1 and ADMA generation as well as placental hypoxia
.
J. Hainan Med. Univ.
22
,
50
53
116.
Galbiati
S.
,
Inversetti
A.
,
Causarano
V.
,
Stenirri
S.
,
Soriani
N.
,
Ambrosi
A.
et al.
(
2015
)
HIF1A and MIF as potential predictive mRNA biomarkers of pre-eclampsia: a longitudinal prospective study in high risk population
.
Clin. Chem. Lab. Med.
53
,
1339
1347
[PubMed]
117.
Zamudio
S.
,
Wu
Y.
,
Ietta
F.
,
Rolfo
A.
,
Cross
A.
,
Wheeler
T.
et al.
(
2007
)
Human placental hypoxia-inducible factor-1alpha expression correlates with clinical outcomes in chronic hypoxia in vivo
.
Am. J. Pathol.
6
,
2171
2179
118.
Rajakumar
A.
,
Whitelock
K.A.
,
Weissfeld
L.A.
,
Daftary
A.R.
,
Markovic
N.
and
Conrad
K.P.
(
2001
)
Selective overexpression of the hypoxia-inducible transcription factor, HIF-2alpha, in placentas from women with preeclampsia
.
Biol. Reprod.
2
,
499
506
119.
Liu
W.
,
Wang
S.J.
and
Lin
Q.D.
(
2014
)
Study on the expressions of PHD and HIF in placentas from normal pregnant women and patients with preeclampsia
.
Int. J. Biol. Sci.
3
,
278
284
120.
Muralimanoharan
S.
,
Guo
C.
,
Myatt
L.
and
Maloyan
A.
(
2015
)
Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity
.
Int. J. Obes (Lond)
8
,
1247
1281
121.
Xuan
R.R.
,
Niu
T.T.
and
Chen
H.M.
(
2016
)
Astaxanthin blocks preeclampsia progression by suppressing oxidative stress and inflammation
.
Mol. Med. Rep.
14
,
2697
2704
[PubMed]
122.
Gong
P.
,
Liu
M.
,
Hong
G.
,
Li
Y.
,
Xue
P.
,
Zheng
M.
et al.
(
2016
)
Curcumin improves LPS-induced preeclampsia-like phenotype in rat by inhibiting the TLR4 signaling pathway
.
Placenta
41
,
45
52
[PubMed]
123.
Xue
P.
,
Zheng
M.
,
Gong
P.
,
Lin
C.
,
Zhou
J.
,
Li
Y.
et al.
(
2015
)
Single administration of ultra-low-dose lipopolysaccharide in rat early pregnancy induces TLR4 activation in the placenta contributing to preeclampsia
.
PLoS ONE
10
,
e0124001
[PubMed]
124.
Aban
M.
,
Cinel
L.
,
Arslan
M.
,
Dilek
U.
,
Kaplanoglu
M.
,
Arpaci
R.
et al.
(
2004
)
Expression of nuclear factor-kappa B and placental apoptosis in pregnancies complicated with intrauterine growth restriction and preeclampsia: an immunohistochemical study
.
Tohoku J. Exp. Med.
3
,
195
202
125.
Dechend
R.
,
Viedt
C.
,
Muller
D.N.
,
Ugele
B.
,
Brandes
R.P.
,
Wallukat
G.
et al.
(
2003
)
AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase
.
Circulation
107
,
1632
1639
[PubMed]
126.
Vaughan
J.E.
and
Walsh
S.W.
(
2012
)
Activation of NF-κB in Placentas of Women with Preeclampsia
.
Hypertens. Pregnancy
2
,
243
251
127.
Muralimanoharan
S.
,
Maloyan
A.
and
Myatt
L.
(
2013
)
Evidence of sexual dimorphism in the placental function with severe preeclampsia
.
Placenta
12
,
1183
1189
128.
Vásárhelyi
B.
,
Cseh
A.
,
Kocsis
I.
,
Treszl
A.
,
Györffy
B.
and
Rigó
J.J.
(
2006
)
Three mechanisms in the pathogenesis of pre-eclampsia suggested by over-represented transcription factor-binding sites detected with comparative promoter analysis
.
Mol. Hum. Reprod.
12
,
31
34
,
Epub 2006 Jan 10. 2006; 1: 31-4
[PubMed]
129.
Vaiman
D.
,
Calicchio
R.
and
Miralles
F.
(
2013
)
Landscape of transcriptional deregulations in the preeclamptic placenta
.
PLoS ONE
6
,
e65498
130.
Goenka
S.
and
Kaplan
M.H.
(
2011
)
Transcriptional regulation by STAT6
.
Immunol. Res.
1
,
87
96
131.
Laresgoiti-Servitje
E.
,
Gomez-Lopez
N.
and
Olson
D.M.
(
2010
)
An immunological insight into the origins of pre-eclampsia
.
Hum. Reprod. Update
16
,
510
524
[PubMed]
132.
Hashemi
V.
,
Dolati
S.
,
Hosseini
A.
,
Gharibi
T.
,
Danaii
S.
and
Yousefi
M.
(
2017
)
Natural killer T cells in Preeclampsia: An updated review
.
Biomed. Pharmacother.
412
418
[PubMed]
133.
Saito
S.
,
Sakai
M.
,
Sasaki
Y.
,
Tanebe
K.
,
Tsuda
H.
and
Michimata
T.
(
1999
)
Quantitative analysis of peripheral blood Th0, Th1, Th2 and the Th1:Th2 cell ratio during normal human pregnancy and preeclampsia
.
Clin. Exp. Immunol.
117
,
550
555
[PubMed]
134.
Ohkuchi
A.
,
Minakami
H.
,
Aoya
T.
,
Haga
T.
,
Kimura
H.
,
Suzuki
M.
et al.
(
2001
)
Expansion of the fraction of Th1 cells in women with preeclampsia: inverse correlation between the percentage of Th1 cells and the plasma level of PAI-2
.
Am. J. Reprod. Immunol.
46
,
252
259
[PubMed]
135.
Pillay
P.
,
Moodley
K.
,
Vatish
M.
,
Moodley
J.
,
Duarte
R.
and
Mackraj
I.
(
2019
)
Exosomal Th1/Th2 cytokines in preeclampsia and HIV-positive preeclamptic women on highly active anti-retroviral therapy
.
Cytokine
125
,
154795
[PubMed]
136.
Ahn
S.
,
Jeong
E.
,
Min
J.W.
,
Kim
E.
,
Choi
S.S.
,
Kim
C.J.
et al.
(
2017
)
Identification of genes dysregulated by elevation of microRNA-210 levels in human trophoblasts cell line, Swan 71
.
Am. J. Reprod. Immunol.
78
,
e12722
137.
Fan
G.L.
,
Wei
H.
and
Wu
R.
(
2016
)
Expressions of STAT4 and STAT6 in placenta and serum of patients with preeclampsia and the significance
.
Maternal Child Health Care China
6
,
1264
1267
138.
Chatterjee
P.
,
Kopriva
S.E.
,
Chiasson
V.L.
,
Young
K.J.
,
Tobin
R.P.
,
Newell-Rogers
K.
et al.
(
2013
)
Interleukin-4 deficiency induces mild preeclampsia in mice
.
J. Hypertens.
7
,
1414
1423
139.
Chatterjee
P.
,
Chiasson
V.L.
,
Seerangan
G.
,
Tobin
R.P.
,
Kopriva
S.E.
,
Newell-Rogers
M.K.
et al.
(
2015
)
Cotreatment with interleukin 4 and interleukin 10 modulates immune cells and prevents hypertension in pregnant mice
.
Am. J. Hypertens.
1
,
135
142
140.
Lai
Z.
,
Kalkunte
S.
and
Sharma
S.
(
2011
)
A critical role of interleukin-10 in modulating hypoxia-induced preeclampsia-like disease in mice
.
Hypertension
57
,
505
514
[PubMed]
141.
Cottrell
J.N.
,
Amaral
L.M.
,
Harmon
A.
,
Cornelius
D.C.
,
Cunningham
M.W.
Jr
,
Vaka
V.R.
et al.
(
2019
)
Interleukin-4 supplementation improves the pathophysiology of hypertension in response to placental ischemia in RUPP rats
.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
316
,
R165
R171
142.
Omu
A.E.
,
Al-Azemi
M.K.
,
Al-Qattan
F.
and
Al-Yatama
M.
(
2004
)
Connection between human leucocyte antigens D region and T helper cytokines in preeclampsia
.
Arch. Gynecol. Obstet.
2
,
79
84
143.
Henriques
C.U.
,
Rice
G.E.
,
Wong
M.H.
and
Bendtzen
K.
(
1998
)
Immunolocalisation of interleukin-4 and interleukin-4 receptor in placenta and fetal membranes in association with pre-term labour and pre-eclampsia
.
Gynecol. Obstet. Invest.
3
,
172
177
144.
Peixoto
A.B.
,
Araujo Júnior
E.
,
Ribeiro
J.U.
,
Rodrigues
D.B.
,
Castro
E.C.
,
Caldas
T.M.
et al.
(
2016
)
Evaluation of inflammatory mediators in the deciduas of pregnant women with pre-eclampsia/eclampsia
.
J. Matern. Fetal Neonatal Med.
1
,
75
79
145.
Gharesi-Fard
B.
,
Mobasher-Nejad
F.
and
Nasri
F.
(
2016
)
The Expression of T-Helper Associated Transcription Factors and Cytokine Genes in Pre-Eclampsia
.
Iran J. Immunol.
4
,
296
308
146.
Wang
S.
,
Aurora
A.B.
,
Johnson
B.A.
,
Qi
X.
,
McAnally
J.
,
Hill
J.A.
et al.
(
2008
)
The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis
.
Dev. Cell
15
,
261
271
,
2008; 2: 261-71
[PubMed]
147.
van Solingen
C.
,
Seghers
L.
,
Bijkerk
R.
,
Duijs
J.M.
,
Roeten
M.K.
,
van Oeveren-Rietdijk
A.M.
et al.
(
2009
)
Antagomir-mediated silencing of endothelial cell specific microRNA-126 impairs ischemia-induced angiogenesis
.
J. Cell. Mol. Med.
8A
,
1577
1585
148.
van Solingen
C.
,
Bijkerk
R.
,
de Boer
H.C.
,
Rabelink
T.J.
and
van Zonneveld
A.J.
(
2015
)
The Role of microRNA-126 in Vascular Homeostasis
.
Curr. Vasc. Pharmacol.
3
,
341
351
149.
Kuhnert
F.
,
Mancuso
M.R.
,
Hampton
J.
,
Stankunas
K.
,
Asano
T.
,
Chen
C.Z.
et al.
(
2008
)
Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126
.
Development
135
,
3989
3993
,
2008; 24: 3989-93
[PubMed]
150.
Fish
J.E.
,
Santoro
M.M.
,
Morton
S.U.
,
Yu
S.
,
Yeh
R.F.
,
Wythe
J.D.
et al.
(
2008
)
miR-126 regulates angiogenic signaling and vascular integrity
.
Dev. Cell
2
,
272
284
151.
Jiang
Y.
,
Wang
H.
,
Li
L.
,
Guo
S.
,
Zhang
L.
and
Cai
J.
(
2014
)
Peripheral blood miRNAs as a biomarker for chronic cardiovascular diseases
.
Sci. Rep.
4
,
5026
[PubMed]
152.
Jin
F.
and
Xing
J.
(
2018
)
Circulating miR-126 and miR-130a levels correlate with lower disease risk, disease severity, and reduced inflammatory cytokine levels in acute ischemic stroke patients
.
Neurol. Sci.
10
,
1757
1765
153.
Wei
X.J.
,
Han
M.
,
Yang
F.Y.
,
Wei
G.C.
,
Liang
Z.G.
,
Yao
H.
et al.
(
2015
)
Biological significance of miR-126 expression in atrial fibrillation and heart failure
.
Braz. J. Med. Biol. Res.
11
,
983
989
154.
Wang
X.
,
Lian
Y.
,
Wen
X.
,
Guo
J.
,
Wang
Z.
,
Jiang
S.
et al.
(
2017
)
Expression of miR-126 and its potential function in coronary artery disease
.
Afr. Health Sci.
2
,
474
480
155.
Liu
Y.
,
Gao
G.
,
Yang
C.
,
Zhou
K.
,
Shen
B.
,
Liang
H.
et al.
(
2014
)
The role of circulating microRNA-126 (miR-126): a novel biomarker for screening prediabetes and newly diagnosed type 2 diabetes mellitus
.
Int. J. Mol. Sci.
6
,
10567
10577
156.
Goerke
S.M.
,
Kiefer
L.S.
,
Stark
G.B.
,
Simunovic
F.
and
Finkenzeller
G.
(
2015
)
miR-126 modulates angiogenic growth parameters of peripheral blood endothelial progenitor cells
.
Biol. Chem.
3
,
245
252
157.
Zhang
Y.
,
Wang
X.
,
Xu
B.
,
Wang
B.
,
Wang
Z.
,
Liang
Y.
et al.
(
2013
)
Epigenetic silencing of miR-126 contributes to tumor invasion and angiogenesis in colorectal cancer
.
Oncol. Rep.
4
,
1976
1984
158.
Zhou
J.
,
Li
Y.S.
,
Nguyen
P.
,
Wang
K.C.
,
Weiss
A.
,
Kuo
Y.C.
et al.
(
2013
)
Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126: role of shear stress
.
Circ. Res.
1
,
40
51
159.
Zernecke
A.
,
Bidzhekov
K.
,
Noels
H.
,
Shagdarsuren
E.
,
Gan
L.
,
Denecke
B.
et al.
(
2009
)
Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection
.
Sci. Signal
100
,
ra81
160.
Zhu
X.
,
Li
H.
,
Long
L.
,
Hui
L.
,
Chen
H.
,
Wang
X.
et al.
(
2012
)
miR-126 enhances the sensitivity of non-small cell lung cancer cells to anticancer agents by targeting vascular endothelial growth factor A
.
Acta Biochim. Biophys. Sin. (Shanghai)
6
,
519
526
161.
Otsubo
T.
,
Akiyama
Y.
,
Hashimoto
Y.
,
Shimada
S.
,
Goto
K.
and
Yuasa
Y.
(
2011
)
MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis
.
PLoS ONE
6
,
e16617
[PubMed]
162.
Lechman
E.R.
,
Gentner
B.
,
van Galen
P.
,
Giustacchini
A.
,
Saini
M.
,
Boccalatte
F.E.
et al.
(
2012
)
Attenuation of miR-126 activity expands HSC in vivo without exhaustion
.
Cell Stem Cell
6
,
799
811
163.
Yan
T.
,
Liu
Y.
,
Cui
K.
,
Hu
B.
,
Wang
F.
and
Zou
L.
(
2013
)
MicroRNA-126 regulates EPCs function: implications for a role of miR-126 in preeclampsia
.
J. Cell. Biochem.
9
,
2148
2159
164.
Oglesby
I.K.
,
Bray
I.M.
,
Chotirmall
S.H.
,
Stallings
R.L.
,
O'Neill
S.J.
,
McElvaney
N.G.
et al.
(
2010
)
miR-126 is downregulated in cystic fibrosis airway epithelial cells and regulates TOM1 expression
.
J. Immunol.
184
,
1702
1709
[PubMed]
165.
Fejes
Z.
,
Poliska
S.
,
Czimmerer
Z.
,
Kaplar
M.
,
Penyige
A.
,
Gal Szabo
G.
et al.
(
2017
)
Hyperglycaemia suppresses microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 diabetes mellitus
.
Thromb. Haemost.
117
,
529
542
[PubMed]
166.
Hua
Y.
,
Liang
C.
,
Miao
C.
,
Wang
S.
,
Su
S.
,
Shao
P.
et al.
(
2018
)
MicroRNA-126 inhibits proliferation and metastasis in prostate cancer via regulation of ADAM9
.
Oncol. Lett.
15
,
9051
9060
[PubMed]
167.
Baldassari
F.
,
Zerbinati
C.
,
Galasso
M.
,
Corra
F.
,
Minotti
L.
,
Agnoletto
C.
et al.
(
2018
)
Screen for MicroRNA and Drug Interactions in Breast Cancer Cell Lines Points to miR-126 as a Modulator of CDK4/6 and PIK3CA Inhibitors
.
Front. Genet.
9
,
174
[PubMed]
168.
Xiong
Y.
,
Kotian
S.
,
Zeiger
M.A.
,
Zhang
L.
and
Kebebew
E.
(
2015
)
miR-126-3p Inhibits Thyroid Cancer Cell Growth and Metastasis, and Is Associated with Aggressive Thyroid Cancer
.
PLoS ONE
10
,
e0130496
[PubMed]
169.
Ishizaki
T.
,
Tamiya
T.
,
Taniguchi
K.
,
Morita
R.
,
Kato
R.
,
Okamoto
F.
et al.
(
2011
)
miR126 positively regulates mast cell proliferation and cytokine production through suppressing Spred1
.
Genes Cells: Dev. Mol. Cell. Mech.
16
,
803
814
170.
Wu
H.
and
Zhang
J.
(
2018
)
miR-126 in Peripheral Blood Mononuclear Cells Negatively Correlates with Risk and Severity and is Associated with Inflammatory Cytokines as well as Intercellular Adhesion Molecule-1 in Patients with Coronary Artery Disease
.
Cardiology
139
,
110
118
[PubMed]
171.
Ye
P.
,
Liu
J.
,
He
F.
,
Xu
W.
and
Yao
K.
(
2013
)
Hypoxia-induced deregulation of miR-126 and its regulative effect on VEGF and MMP-9 expression
.
Int. J. Med. Sci.
1
,
17
23
172.
Mondadori dos Santos
A.
,
Metzinger
L.
,
Haddad
O.
,
M'baya-Moutoula
E.
,
Taïbi
F.
,
Charnaux
N.
et al.
(
2015
)
miR-126 Is Involved in Vascular Remodeling under Laminar Shear Stress
.
Biomed. Res. Int.
497280
[PubMed]
173.
Hemmings
B.A.
and
Restuccia
D.F.
(
2012
)
PI3K-PKB/Akt pathway
.
Cold Spring Harb. Perspect. Biol.
4
,
a011189
[PubMed]
174.
Xiao
J.
,
Lin
H.Y.
,
Zhu
Y.Y.
,
Zhu
Y.P.
and
Chen
L.W.
(
2016
)
MiR-126 regulates proliferation and invasion in the bladder cancer BLS cell line by targeting the PIK3R2-mediated PI3K/Akt signaling pathway
.
Onco. Targets Ther.
9
,
5181
5193
[PubMed]
175.
Wu
X.J.
,
Zhao
Z.F.
,
Kang
X.J.
,
Wang
H.J.
,
Zhao
J.
and
Pu
X.M.
(
2016
)
MicroRNA-126-3p suppresses cell proliferation by targeting PIK3R2 in Kaposi's sarcoma cells
.
Oncotarget
7
,
36614
36621
[PubMed]
176.
Song
L.
,
Li
D.
,
Gu
Y.
,
Wen
Z.M.
,
Jie
J.
,
Zhao
D.
et al.
(
2016
)
MicroRNA-126 Targeting PIK3R2 Inhibits NSCLC A549 Cell Proliferation, Migration, and Invasion by Regulation of PTEN/PI3K/AKT Pathway
.
Clin. Lung Cancer
17
,
e65
e75
[PubMed]
177.
Qu
Y.
,
Wu
J.
,
Deng
J.X.
,
Zhang
Y.P.
,
Liang
W.Y.
,
Jiang
Z.L.
et al.
(
2016
)
MicroRNA-126 affects rheumatoid arthritis synovial fibroblast proliferation and apoptosis by targeting PIK3R2 and regulating PI3K-AKT signal pathway
.
Oncotarget
7
,
74217
74226
[PubMed]
178.
Meng
Q.
,
Wang
W.
,
Yu
X.
,
Li
W.
,
Kong
L.
,
Qian
A.
et al.
(
2015
)
Upregulation of MicroRNA-126 Contributes to Endothelial Progenitor Cell Function in Deep Vein Thrombosis via Its Target PIK3R2
.
J. Cell. Biochem.
116
,
1613
1623
[PubMed]
179.
Zhang
J.
,
Zhang
Z.
,
Zhang
D.Y.
,
Zhu
J.
,
Zhang
T.
and
Wang
C.
(
2013
)
microRNA 126 inhibits the transition of endothelial progenitor cells to mesenchymal cells via the PIK3R2-PI3K/Akt signalling pathway
.
PLoS ONE
8
,
e83294
[PubMed]
180.
Triche
E.W.
,
Uzun
A.
,
DeWan
A.T.
,
Kurihara
I.
,
Liu
J.
,
Occhiogrosso
R.
et al.
(
2014
)
Bioinformatic approach to the genetics of preeclampsia
.
Obstet. Gynecol.
123
,
1155
1161
[PubMed]
181.
Hu
Y.
,
Li
P.
,
Hao
S.
,
Liu
L.
,
Zhao
J.
and
Hou
Y.
(
2009
)
Differential expression of microRNAs in the placentae of Chinese patients with severe pre-eclampsia
.
Clin. Chem. Lab. Med.
8
,
923
929
182.
Hong
F.
,
Li
Y.
and
Xu
Y.
(
2014
)
Decreased placental miR-126 expression and vascular endothelial growth factor levels in patients with pre-eclampsia
.
J. Int. Med. Res.
6
,
1243
1251
183.
Yang
S.
,
Li
H.
,
Ge
Q.
,
Guo
L.
and
Chen
F.
(
2015
)
Deregulated microRNA species in the plasma and placenta of patients with preeclampsia
.
Mol. Med. Rep.
1
,
527
534
184.
Xu
J.
,
Gu
Y.
,
Lewis
D.F.
,
Cooper
D.B.
,
McCathran
C.E.
and
Wang
Y.
,
Downregulation of VDR and miR-126-3p expression contributes to increased endothelial inflammatory response in preeclampsia
.
Am. J. Reprod. Immunol.
2019
,
e13172
185.
Jean
S.
and
Kiger
A.A.
(
2014
)
Classes of phosphoinositide 3-kinases at a glance
.
J. Cell Sci.
127
,
923
928
[PubMed]
186.
Sessa
R.
,
Seano
G.
,
di Blasio
L.
,
Gagliardi
P.A.
,
Isella
C.
,
Medico
E.
et al.
(
2012
)
The miR-126 regulates angiopoietin-1 signaling and vessel maturation by targeting p85beta
.
Biochim. Biophys. Acta
1823
,
1925
1935
[PubMed]
187.
Dong
X.
and
Shi
D.
(
2017
)
Simvastatin Alleviates Pathology in a Rat Model of Preeclampsia Involving ERK/MAPK Pathway
.
Reprod. Sci.
7
,
1053
1061
188.
Zhou
J.
,
Miao
H.
,
Li
X.
,
Hu
Y.
,
Sun
H.
and
Hou
Y.
(
2017
)
Curcumin inhibits placental inflammation to ameliorate LPS-induced adverse pregnancy outcomes in mice via upregulation of phosphorylated Akt
.
Inflamm. Res.
2
,
177
185
189.
Tian
M.
,
Zhang
Y.
,
Liu
Z.
,
Sun
G.
,
Mor
G.
and
Liao
A.
(
2016
)
The PD-1/PD-L1 inhibitory pathway is altered in pre-eclampsia and regulates T cell responses in pre-eclamptic rats
.
Sci. Rep.
6
,
27683
[PubMed]
190.
Khaliq
O.P.
,
Murugesan
S.
,
Moodley
J.
and
Mackraj
I.
(
2018
)
Differential expression of miRNAs are associated with the insulin signaling pathway in preeclampsia and gestational hypertension
.
Clin. Exp. Hypertension (New York, N.Y.: 1993)
40
,
744
751
191.
Cudmore
M.J.
,
Ahmad
S.
,
Sissaoui
S.
,
Ramma
W.
,
Ma
B.
,
Fujisawa
T.
et al.
(
2012
)
Loss of Akt activity increases circulating soluble endoglin release in preeclampsia: identification of inter-dependency between Akt-1 and heme oxygenase-1
.
Eur. Heart J.
9
,
1150
1158
192.
Kaitu'u-Lino
T.J.
,
Hastie
R.
,
Hannan
N.J.
,
Brownfoot
F.
,
De Silva
M.
,
Cannon
P.
et al.
(
2016
)
Loss of Akt increases soluble endoglin release from endothelial cells but not placenta
.
Pregnancy Hypertension
2
,
95
102
193.
Park
J.K.
,
Jeong
J.W.
,
Kang
M.Y.
,
Baek
J.C.
,
Shin
J.K.
,
Lee
S.A.
et al.
(
2010
)
Inhibition of the PI3K-Akt pathway suppresses sFlt1 expression in human placental hypoxia models in vitro
.
Placenta
31
,
621
629
[PubMed]
194.
Yung
H.W.
,
Atkinson
D.
,
Campion-Smith
T.
,
Olovsson
M.
,
Charnock-Jones
D.S.
and
Burton
G.J.
(
2014
)
Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia
.
J. Pathol.
2
,
262
276
195.
Orcy
R.B.
,
Schroeder
S.
,
Martins-Costa
S.H.
,
Ramos
J.G.
,
Schechinger
W.
,
Klein
H.
et al.
(
2008
)
Signalization of Akt/PKB in the placenta, skeletal muscle and adipose tissue of preeclampsia patients
.
Gynecol. Obstet. Invest.
4
,
231
236
196.
Friedrich
M.
,
Pracht
K.
,
Mashreghi
M.F.
,
Jack
H.M.
,
Radbruch
A.
and
Seliger
B.
(
2017
)
The role of the miR-148/-152 family in physiology and disease
.
Eur. J. Immunol.
47
,
2026
2038
[PubMed]
197.
Zhu
A.
,
Xia
J.
,
Zuo
J.
,
Jin
S.
,
Zhou
H.
,
Yao
L.
et al.
(
2012
)
MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in gastric cancer
.
Med. Oncol.
29
,
2701
2709
[PubMed]
198.
Sui
C.
,
Meng
F.
,
Li
Y.
and
Jiang
Y.
(
2015
)
miR-148b reverses cisplatin-resistance in non-small cell cancer cells via negatively regulating DNA (cytosine-5)-methyltransferase 1(DNMT1) expression
.
J. Transl. Med.
13
,
132
[PubMed]
199.
Xiang
Y.
,
Ma
N.
,
Wang
D.
,
Zhang
Y.
,
Zhou
J.
,
Wu
G.
et al.
(
2014
)
MiR-152 and miR-185 co-contribute to ovarian cancer cells cisplatin sensitivity by targeting DNMT1 directly: a novel epigenetic therapy independent of decitabine
.
Oncogene
33
,
378
386
[PubMed]
200.
Huang
J.
,
Wang
Y.
,
Guo
Y.
and
Sun
S.
(
2010
)
Down-regulated microRNA-152 induces aberrant DNA methylation in hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1
.
Hepatol. (Baltimore, Md)
52
,
60
70
[PubMed]
201.
Mutze
K.
,
Langer
R.
,
Schumacher
F.
,
Becker
K.
,
Ott
K.
,
Novotny
A.
et al.
(
2011
)
DNA methyltransferase 1 as a predictive biomarker and potential therapeutic target for chemotherapy in gastric cancer
.
Eur. J. Cancer
47
,
1817
1825
[PubMed]
202.
Yan
F.
,
Shen
N.
,
Pang
J.
,
Zhao
N.
,
Deng
B.
,
Li
B.
et al.
(
2017
)
A regulatory circuit composed of DNA methyltransferases and receptor tyrosine kinases controls lung cancer cell aggressiveness
.
Oncogene
36
,
6919
6928
[PubMed]
203.
Gu
Y.
,
Yang
P.
,
Shao
Q.
,
Liu
X.
,
Xia
S.
,
Zhang
M.
et al.
(
2013
)
Investigation of the expression patterns and correlation of DNA methyltransferases and class I histone deacetylases in ovarian cancer tissues
.
Oncol. Lett.
5
,
452
458
[PubMed]
204.
Fan
H.
,
Zhao
Z.J.
,
Cheng
J.
,
Su
X.W.
,
Wu
Q.X.
and
Shan
Y.F.
(
2009
)
Overexpression of DNA methyltransferase 1 and its biological significance in primary hepatocellular carcinoma
.
World J. Gastroenterol.
15
,
2020
2026
[PubMed]
205.
Yuan
K.
,
Lian
Z.
,
Sun
B.
,
Clayton
M.M.
,
Ng
I.O.
and
Feitelson
M.A.
(
2012
)
Role of miR-148a in hepatitis B associated hepatocellular carcinoma
.
PLoS ONE
7
,
e35331
[PubMed]
206.
Zhu
X.M.
,
Han
T.
,
Wang
X.H.
,
Li
Y.H.
,
Yang
H.G.
,
Luo
Y.N.
et al.
(
2010
)
Overexpression of miR-152 leads to reduced expression of human leukocyte antigen-G and increased natural killer cell mediated cytolysis in JEG-3 cells
.
Am. J. Obstet. Gynecol.
202
,
592.e1
597.e1
207.
Tan
Z.
,
Randall
G.
,
Fan
J.
,
Camoretti-Mercado
B.
,
Brockman-Schneider
R.
,
Pan
L.
et al.
(
2007
)
Allele-specific targeting of microRNAs to HLA-G and risk of asthma
.
Am. J. Hum. Genet.
81
,
829
834
[PubMed]
208.
Manaster
I.
,
Goldman-Wohl
D.
,
Greenfield
C.
,
Nachmani
D.
,
Tsukerman
P.
,
Hamani
Y.
et al.
(
2012
)
MiRNA-mediated control of HLA-G expression and function
.
PLoS ONE
7
,
e33395
[PubMed]
209.
Durmanova
V.
,
Homolova
M.
,
Drobny
J.
,
Shawkatova
I.
and
Buc
M.
(
2013
)
Role of HLA-G and other immune mechanisms in pregnancy
.
Open Life Sci.
8
,
226
239
210.
Zhang
L.
,
Yuan
J.M.
,
Zhao
R.H.
,
Wang
L.M.
and
Tu
Z.B.
(
2019
)
Correlation of MiR-152 expression with VEGF expression in placental tissue of preeclampsia rat and its influence on apoptosis of trophoblast cells
.
Eur. Rev. Med. Pharmacol. Sci.
23
,
3553
3560
[PubMed]
211.
Zhao
G.
,
Zhou
X.
,
Chen
S.
,
Miao
H.
,
Fan
H.
,
Wang
Z.
et al.
(
2014
)
Differential expression of microRNAs in decidua-derived mesenchymal stem cells from patients with pre-eclampsia
.
J. Biomed. Sci.
21
,
81
[PubMed]
212.
Lim
D.H.K.
and
Maher
E.R.
(
2010
)
DNA methylation: a form of epigenetic control of gene expression
.
Obstet. Gynaecol.
12
,
37
42
213.
Anderson
C.M.
,
Ralph
J.L.
,
Wright
M.L.
,
Linggi
B.
and
Ohm
J.E.
(
2014
)
DNA methylation as a biomarker for preeclampsia
.
Biol. Res. Nurs.
4
,
409
420
214.
Kulkarni
A.
,
Chavan-Gautam
P.
,
Mehendale
S.
,
Yadav
H.
and
Joshi
S.
(
2011
)
Global DNA methylation patterns in placenta and its association with maternal hypertension in pre-eclampsia
.
DNA Cell Biol.
2
,
79
84
215.
Ching
T.
,
Song
M.A.
,
Tiirikainen
M.
,
Molnar
J.
,
Berry
M.
,
Towner
D.
et al.
(
2014
)
Genome-wide hypermethylation coupled with promoter hypomethylation in the chorioamniotic membranes of early onset pre-eclampsia
.
Mol. Hum. Reprod.
9
,
885
904
216.
Blair
J.D.
,
Yuen
R.K.
,
Lim
B.K.
,
McFadden
D.E.
,
von Dadelszen
P.
and
Robinson
W.P.
(
2013
)
Widespread DNA hypomethylation at gene enhancer regions in placentas associated with early-onset pre-eclampsia
.
Mol. Hum. Reprod.
10
,
697
708
217.
Yuen
R.K.
,
Peñaherrera
M.S.
,
von Dadelszen
P.
,
McFadden
D.E.
and
Robinson
W.P.
(
2010
)
DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia
.
Eur. J. Hum. Genet.
9
,
1006
1012
218.
Zhu
L.
,
Lv
R.
,
Kong
L.
,
Cheng
H.
,
Lan
F.
and
Li
X.
(
2015
)
Genome-Wide Mapping of 5mC and 5hmC Identified Differentially Modified Genomic Regions in Late-Onset Severe Preeclampsia: A Pilot Study
.
PLoS ONE
7
,
e0134119
219.
Gao
W.L.
,
Li
D.
,
Xiao
Z.X.
,
Liao
Q.P.
,
Yang
H.X.
,
Li
Y.X.
et al.
(
2011
)
Detection of global DNA methylation and paternally imprinted H19 gene methylation in preeclamptic placentas
.
Hypertens. Res.
5
,
655
661
220.
Jia
R.Z.
,
Zhang
X.
,
Hu
P.
,
Liu
X.M.
,
Hua
X.D.
,
Wang
X.
et al.
(
2012
)
Screening for differential methylation status in human placenta in preeclampsia using a CpG island plus promoter microarray
.
Int. J. Mol. Med.
1
,
133
141
221.
Wang
Z.
,
Lu
S.
,
Liu
C.
,
Zhao
B.
,
Pei
K.
,
Tian
L.
et al.
(
2010
)
Expressional and epigenetic alterations of placental matrix metalloproteinase 9 in preeclampsia
.
Gynecol. Endocrinol.
2
,
96
102
222.
Huang
A.
,
Wu
H.
,
Iriyama
T.
,
Zhang
Y.
,
Sun
K.
,
Song
A.
et al.
(
2017
)
Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia
.
Hypertension (Dallas, Tex: 1979)
1
,
209
218
223.
Furuhashi
M.
,
Saitoh
S.
,
Shimamoto
K.
and
Miura
T.
(
2014
)
Fatty Acid-Binding Protein 4 (FABP4): Pathophysiological Insights and Potent Clinical Biomarker of Metabolic and Cardiovascular Diseases
.
Clin. Med. Insights Cardiol.
8
,
23
33
[PubMed]
224.
Xu
A.
,
Wang
Y.
,
Xu
J.Y.
,
Stejskal
D.
,
Tam
S.
,
Zhang
J.
et al.
(
2006
)
Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome
.
Clin. Chem.
52
,
405
413
[PubMed]
225.
Tso
A.W.
,
Xu
A.
,
Sham
P.C.
,
Wat
N.M.
,
Wang
Y.
,
Fong
C.H.
et al.
(
2007
)
Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort
.
Diabetes Care
30
,
2667
2672
[PubMed]
226.
Nakamura
R.
,
Okura
T.
,
Fujioka
Y.
,
Sumi
K.
,
Matsuzawa
K.
,
Izawa
S.
et al.
(
2017
)
Serum fatty acid-binding protein 4 (FABP4) concentration is associated with insulin resistance in peripheral tissues, A clinical study
.
PLoS ONE
12
,
e0179737
[PubMed]
227.
Ota
H.
,
Furuhashi
M.
,
Ishimura
S.
,
Koyama
M.
,
Okazaki
Y.
,
Mita
T.
et al.
(
2012
)
Elevation of fatty acid-binding protein 4 is predisposed by family history of hypertension and contributes to blood pressure elevation
.
Am. J. Hypertens.
25
,
1124
1130
[PubMed]
228.
Yeung
D.C.
,
Xu
A.
,
Cheung
C.W.
,
Wat
N.M.
,
Yau
M.H.
,
Fong
C.H.
et al.
(
2007
)
Serum adipocyte fatty acid-binding protein levels were independently associated with carotid atherosclerosis
.
Arterioscler. Thromb. Vasc. Biol.
27
,
1796
1802
[PubMed]
229.
Scifres
C.M.
,
Chen
B.
,
Nelson
D.M.
and
Sadovsky
Y.
(
2011
)
Fatty acid binding protein 4 regulates intracellular lipid accumulation in human trophoblasts
.
J. Clin. Endocrinol. Metab.
96
,
E1083
E1091
[PubMed]
230.
Tuuri
A.L.
,
Jauhiainen
M.S.
,
Tikkanen
M.J.
and
Kaaja
R.J.
(
2014
)
Systolic blood pressure and fatty acid-binding protein 4 predict pregnancy-induced hypertension in overweight nulliparous women
.
Placenta
35
,
797
801
[PubMed]
231.
Fasshauer
M.
,
Seeger
J.
,
Waldeyer
T.
,
Schrey
S.
,
Ebert
T.
,
Kratzsch
J.
et al.
(
2008
)
Serum levels of the adipokine adipocyte fatty acid-binding protein are increased in preeclampsia
.
Am. J. Hypertens.
5
,
582
586
232.
Shangguan
X.
,
Liu
F.
,
Wang
H.
,
He
J.
and
Dong
M.
(
2009
)
Alterations in serum adipocyte fatty acid binding protein and retinol binding protein-4 in normal pregnancy and preeclampsia
.
Clin. Chim. Acta
407
,
58
61
[PubMed]
233.
Xiong
J.
,
Ding
N.
,
Gao
T.
,
Wang
Y.
,
Guo
W.
,
Zhang
H.
et al.
(
2018
)
Hypermethylation of endoplasmic reticulum disulfide oxidase 1α leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia
.
J. Cell. Biochem.
10
,
8588
8599
234.
Ye
Y.
,
Tang
Y.
,
Xiong
Y.
,
Feng
L.
and
Xiaotian
L.
(
2018
)
Bisphenol A exposure alters placentation and causes preeclampsia-like features in pregnant mice involved in reprogramming of DNA methylation of WNT2
.
FASEB J.
fj201800934RRR
235.
Ma
M.
,
Zhou
Q.
,
Xiong
Y.
,
Li
B.
and
Li
X.
(
2018
)
Preeclampsia is associated with hypermethylation of IGF-1 promoter mediated by DNMT1
.
Am. J. Transl. Res.
1
,
16
39
236.
Tang
Y.
,
Liu
H.
,
Li
H.
,
Peng
T.
,
Gu
W.
and
Li
X.
(
2015
)
Hypermethylation of the HLA-G promoter is associated with preeclampsia
.
Mol. Hum. Reprod.
9
,
736
744
237.
Zhuang
X.W.
,
Li
J.
,
Brost
B.C.
,
Xia
X.Y.
,
Chen
H.B.
,
Wang
C.X.
et al.
(
2014
)
Decreased expression and altered methylation of syncytin-1 gene in human placentas associated with preeclampsia
.
Curr. Pharm. Des.
11
,
1796
1802
238.
Wilson
S.L.
,
Liu
Y.
and
Robinson
W.P.
(
2016
)
Placental telomere length decline with gestational age differs by sex and TERT, DNMT1, and DNMT3A DNA methylation
.
Placenta
26
33
[PubMed]
239.
Watson
C.J.
,
Collier
P.
,
Tea
I.
,
Neary
R.
,
Watson
J.A.
,
Robinson
C.
et al.
(
2014
)
Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype
.
Hum. Mol. Genet.
23
,
2176
2188
[PubMed]
240.
Yan
Y.
,
Peng
H.
,
Wang
P.
,
Wang
H.
and
Dong
M.
(
2016
)
Increased expression of fatty acid binding protein 4 in preeclamptic Placenta and its relevance to preeclampsia
.
Placenta
39
,
94
100
[PubMed]
241.
Lin
Y.P.
,
Xu
C.L.
,
Lin
K.S.
,
Gu
H.B.
,
Chen
L.
,
Wang
Y.
et al.
(
2018
)
Study on the correlation between adipocyte fatty-acid binding protein, glucolipid metabolism, and pre-eclampsia
.
J. Obstet. Gynaecol. Res.
44
,
655
662
[PubMed]
242.
Qiao
G.H.
and
Sun
X.Z.
(
2018
)
Increased plasma fatty acid binding protein 4 concentration at the first prenatal visit and its relevance to preeclampsia
.
Hypertens. Res.
41
,
763
769
[PubMed]
243.
Scifres
C.M.
,
Catov
J.M.
and
Simhan
H.
(
2012
)
Maternal serum fatty acid binding protein 4 (FABP4) and the development of preeclampsia
.
J. Clin. Endocrinol. Metab.
97
,
E349
E356
[PubMed]
244.
Wotherspoon
A.C.
,
Young
I.S.
,
McCance
D.R.
,
Patterson
C.C.
,
Maresh
M.J.
,
Pearson
D.W.
et al.
(
2016
)
Serum Fatty Acid Binding Protein 4 (FABP4) Predicts Pre-eclampsia in Women With Type 1 Diabetes
.
Diabetes Care
39
,
1827
1829
[PubMed]
245.
Jadoon
A.
,
Cunningham
P.
and
McDermott
L.C.
(
2015
)
Regulation of fatty acid binding proteins by hypoxia inducible factors 1α and 2α in the placenta: relevance to pre-eclampsia
.
Prostaglandins Leukot. Essent. Fatty Acids
93
,
25
29
[PubMed]
246.
Hanna
J.
,
Hossain
G.S.
and
Kocerha
J.
(
2019
)
The Potential for microRNA Therapeutics and Clinical Research
.
Front. Genet.
10
,
[PubMed]
247.
Chakraborty
C.
,
Sharma
A.R.
,
Sharma
G.
,
Doss
C.G.P.
and
Lee
S.S.
(
2017
)
Therapeutic miRNA and siRNA: Moving from Bench to Clinic as Next Generation Medicine
.
Mol. Ther. Nucleic Acids
8
,
132
143
[PubMed]
248.
Ling
H.
(
2016
)
Non-coding RNAs: Therapeutic Strategies and Delivery Systems
.
Adv. Exp. Med. Biol.
937
,
229
237
[PubMed]
249.
To
K.K.W.
,
Fong
W.
,
Tong
C.W.S.
,
Wu
M.
,
Yan
W.
and
Cho
W.C.S.
(
2019
)
Advances in the discovery of microRNA-based anticancer therapeutics: latest tools and developments
.
Exp. Opin Drug Discov.
15
,
63
83
250.
Montgomery
R.L.
,
Hullinger
T.G.
,
Semus
H.M.
,
Dickinson
B.A.
,
Seto
A.G.
,
Lynch
J.M.
et al.
(
2011
)
Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure
.
Circulation
124
,
1537
1547
[PubMed]
251.
Benton
S.J.
,
Leavey
K.
,
Grynspan
D.
,
Cox
B.J.
and
Bainbridge
S.A.
(
2018
)
The clinical heterogeneity of preeclampsia is related to both placental gene expression and placental histopathology
.
Am. J. Obstet. Gynecol.
219
,
604.e1
604.e25
252.
Murtoniemi
K.
,
Villa
P.M.
,
Matomäki
J.
,
Keikkala
E.
,
Vuorela
P.
,
Hämäläinen
E.
et al.
(
2018
)
Prediction of pre-eclampsia and its subtypes in high-risk cohort: hyperglycosylated human chorionic gonadotropin in multivariate models
.
BMC Pregnancy Childbirth
18
,
279
[PubMed]
253.
Ogge
G.
,
Chaiworapongsa
T.
,
Romero
R.
,
Hussein
Y.
,
Kusanovic
J.P.
,
Yeo
L.
et al.
(
2011
)
Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia
.
J. Perinat. Med.
39
,
641
652
[PubMed]
254.
Chaiworapongsa
T.
,
Romero
R.
,
Whitten
A.
,
Tarca
A.L.
,
Bhatti
G.
,
Draghici
S.
et al.
(
2013
)
Differences and similarities in the transcriptional profile of peripheral whole blood in early and late-onset preeclampsia: insights into the molecular basis of the phenotype of preeclampsiaa
.
J. Perinat. Med.
41
,
485
504
[PubMed]
255.
Awamleh
Z.
,
Gloor
G.B.
and
Han
V.K.M.
(
2019
)
Placental microRNAs in pregnancies with early onset intrauterine growth restriction and preeclampsia: potential impact on gene expression and pathophysiology
.
BMC Med. Genet.
12
,
91
[PubMed]
256.
Sitras
V.
,
Paulssen
R.H.
,
Gronaas
H.
,
Leirvik
J.
,
Hanssen
T.A.
,
Vartun
A.
et al.
(
2009
)
Differential placental gene expression in severe preeclampsia
.
Placenta
30
,
424
433
[PubMed]
257.
Junus
K.
,
Centlow
M.
,
Wikstrom
A.K.
,
Larsson
I.
,
Hansson
S.R.
and
Olovsson
M.
(
2012
)
Gene expression profiling of placentae from women with early- and late-onset pre-eclampsia: down-regulation of the angiogenesis-related genes ACVRL1 and EGFL7 in early-onset disease
.
Mol. Hum. Reprod.
18
,
146
155
[PubMed]
258.
Lykoudi
A.
,
Kolialexi
A.
,
Lambrou
G.I.
,
Braoudaki
M.
,
Siristatidis
C.
,
Papaioanou
G.K.
et al.
(
2018
)
Dysregulated placental microRNAs in Early and Late onset Preeclampsia
.
Placenta
61
,
24
32
[PubMed]
259.
Pineles
B.L.
,
Romero
R.
,
Montenegro
D.
,
Tarca
A.L.
,
Han
Y.M.
,
Kim
Y.M.
et al.
(
2007
)
Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia
.
Am. J. Obstet. Gynecol.
196
,
261.e1
261.e6
260.
Yang
Q.
,
Lu
J.
,
Wang
S.
,
Li
H.
,
Ge
Q.
and
Lu
Z.
(
2011
)
Application of next-generation sequencing technology to profile the circulating microRNAs in the serum of preeclampsia versus normal pregnant women
.
Clin. Chim. Acta
412
,
2167
2173
[PubMed]
261.
Kotlabova
K.
,
Doucha
J.
and
Hromadnikova
I.
(
2011
)
Placental-specific microRNA in maternal circulation – identification of appropriate pregnancy-associated microRNAs with diagnostic potential
.
J. Reprod. Immunol.
89
,
185
191
[PubMed]
262.
Miura
K.
,
Miura
S.
,
Yamasaki
K.
,
Higashijima
A.
,
Kinoshita
A.
,
Yoshiura
K.-I.
et al.
(
2010
)
Identification of Pregnancy-Associated MicroRNAs in Maternal Plasma
.
Clin. Chem.
56
,
1767
1771
[PubMed]
263.
Hromadnikova
I.
,
Kotlabova
K.
,
Doucha
J.
,
Dlouha
K.
and
Krofta
L.
(
2012
)
Absolute and relative quantification of placenta-specific micrornas in maternal circulation with placental insufficiency-related complications
.
J. Mol. Diagn.
14
,
160
167
[PubMed]
264.
Herrera-Carrillo
E.
,
Liu
Y.P.
and
Berkhout
B.
(
2017
)
Improving miRNA Delivery by Optimizing miRNA Expression Cassettes in Diverse Virus Vectors
.
Hum. Gene Ther. Methods
28
,
177
190
[PubMed]
265.
Bai
Z.
,
Wei
J.
,
Yu
C.
,
Han
X.
,
Qin
X.
,
Zhang
C.
et al.
(
2019
)
Non-viral nanocarriers for intracellular delivery of microRNA therapeutics
.
J. Mater. Chem. B
7
,
1209
1225
[PubMed]
266.
Beards
F.
,
Jones
L.E.
,
Charnock
J.
,
Forbes
K.
and
Harris
L.K.
(
2017
)
Placental Homing Peptide-microRNA Inhibitor Conjugates for Targeted Enhancement of Intrinsic Placental Growth Signaling
.
Theranostics
7
,
2940
2955
[PubMed]
267.
Kang
Y.J.
,
Lees
M.
,
Matthews
L.C.
,
Kimber
S.J.
,
Forbes
K.
and
Aplin
J.D.
(
2015
)
MiR-145 suppresses embryo-epithelial juxtacrine communication at implantation by modulating maternal IGF1R
.
J. Cell Sci.
128
,
804
814
[PubMed]
268.
Farrokhnia
F.
,
Aplin
J.D.
,
Westwood
M.
and
Forbes
K.
(
2014
)
MicroRNA regulation of mitogenic signaling networks in the human placenta
.
J. Biol. Chem.
289
,
30404
30416
[PubMed]
269.
Keniry
A.
,
Oxley
D.
,
Monnier
P.
,
Kyba
M.
,
Dandolo
L.
,
Smits
G.
et al.
(
2012
)
The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r
.
Nat. Cell Biol.
14
,
659
665
[PubMed]
270.
Gao
W.L.
,
Liu
M.
,
Yang
Y.
,
Yang
H.
,
Liao
Q.
,
Bai
Y.
et al.
(
2012
)
The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1)
.
RNA Biol
9
,
1002
1010
[PubMed]
271.
Hromadnikova
I.
,
Kotlabova
K.
,
Hympanova
L.
and
Krofta
L.
(
2015
)
Cardiovascular and Cerebrovascular Disease Associated microRNAs Are Dysregulated in Placental Tissues Affected with Gestational Hypertension, Preeclampsia and Intrauterine Growth Restriction
.
PLoS ONE
10
,
e0138383
[PubMed]
272.
King
A.
,
Ndifon
C.
,
Lui
S.
,
Widdows
K.
,
Kotamraju
V.R.
,
Agemy
L.
et al.
(
2016
)
Tumor-homing peptides as tools for targeted delivery of payloads to the placenta
.
Sci. Adv.
2
,
e1600349
e1600349
[PubMed]
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).