The discovery of endothelial progenitor cells (EPCs), a group of cells that play important roles in angiogenesis and the maintenance of vascular endothelial integrity, has led to considerable improvements in our understanding of the circulatory system and the regulatory mechanisms of vascular homoeostasis. Despite lingering disputes over where EPCs actually originate and how they facilitate angiogenesis, extensive research in the past decade has brought about significant advancements in this field of research, establishing EPCs as an essential element in the pathogenesis of various diseases. EPC and hypertensive disorders, especially essential hypertension (EH, also known as primary hypertension), represent one of the most appealing branches in this area of research. Chronic hypertension remains a major threat to public health, and the exact pathologic mechanisms of EH have never been fully elucidated. Is there a relationship between EPC and hypertension? If so, what is the nature of such relationship–is it mediated by blood pressure alterations, or other factors that lie in between? How can our current knowledge about EPCs be utilized to advance the prevention and clinical management of hypertension? In this review, we set out to answer these questions by summarizing the current concepts about EPC pathophysiology in the context of hypertension, while attempting to point out directions for future research on this subject.

INTRODUCTION

Hypertension is one of the most prevalent diseases worldwide. By the latest statistics, approximately 80 million adults in the United States currently suffer from hypertension, and over 8% of death from all causes is attributable to high blood pressure [1]. Although an elevation of blood pressure can be caused by a variety of factors, the aetiology of chronic hypertension is unclear in over 85% of patients. These patients are referred to as having essential hypertension (EH), a disease that remains, to date, one of the major risk factors of many cardiovascular diseases. EH constitutes a serious burden on public health because there is no definitive cure for the disease. This can lead to patients being permanently dependent on medications and susceptible to long-term cardiovascular complications. Owing to the complex and multi-systemic nature of its development, multiple hypotheses have been generated within the medical literature to explain the pathogenesis of EH and the associated damage to target organs [2]. Among these, a widely accepted theory is that functional and structural alterations of the endothelium have an indispensable role in the development of various target organ damage and adverse cardiovascular outcomes in hypertension [3]. Nevertheless, the relationship between hypertension and endothelial dysfunction can be somewhat puzzling–which of them is the victim, and which is the culprit [4]? It was not until the discovery of endothelial progenitor cells (EPCs) that more missing pieces of this puzzle became identified. First revealed in 1997 by Asahara et al. [5], EPCs were initially believed to be a group of cells derived from the bone marrow that participated in the generation and repair of the vascular endothelium. It was not long after this pioneering study that the correlation between EPC biological abnormalities and elevated risks of adverse cardiovascular outcomes was demonstrated [6,7], leading to the assumption that the impairment of EPCs may account for hypertension-related target organ damage. Hypertension was later proven to be the most important independent predictor of EPC functional decline in patients with coronary artery diseases [8], and a series of ensuing studies have further supported the significance of the association between EPC and hypertension [9,10]. However, as more data accumulate, it turned out that the association between EPCs, hypertension and cardiovascular outcomes is far more complicated than we had previously thought–different types of EPCs may have distinct pathogenetic roles, different stages of hypertension might have different associations with EPCs, and, furthermore, there exist complex regulatory mechanisms that mediate the hypertension–EPC relationship. This necessitates a thorough summary of what is currently known and what remains unresolved in this field.

The aim of this article is to provide an in-depth review focusing on the recent concepts about EPC dysregulation and hypertension, and highlighting their implications for future research. It needs to be noted that EPC is now an inclusive definition of a broad spectrum of cells. As such, their involvement in various diseases differs significantly. Therefore, given the scope of this review, emphasis can only be placed on the aspects of EPCs that are most relevant to hypertension (specifically EH), and this article will be intentionally limited in addressing other topics in this area (including certain secondary hypertensive disorders such as pregnancy related hypertension) that may as well be of significance, but are relatively less pertinent.

A CONCISE PRIMER OF EPC BIOLOGY

Aside from cardiovascular medicine, the biology of EPCs has also been studied substantially in many other areas of research, such as haematology/oncology [11]. As a result, our knowledge about the characterization of EPCs and their mechanistic roles in vascular homoeostasis and regeneration is constantly being revised. Considering the theme of this review, in this section, information on some of the cutting-edge findings in basic EPC research (which is available elsewhere [12]) might be left out, and emphasis will be placed on presenting a conventional model of EPCs’ participation in angiogenesis–from their origin in the bone marrow, to the migration in the peripheral circulation and finally to their functioning at sites in the vascular endothelium. Certain points about the culturing, quantifying and functional testing methods essential to the understanding of EPC behaviour in hypertension will also be covered.

Definition of EPC

Prior to any discussions in this section, there is a need that the issue regarding the use of the term EPC be addressed. Although the initial use of EPC in naming immature precursor cells that bore the capability of differentiating into endothelial cells was literally accurate, EPCs have now been proven to actually be a heterogeneous group of cells that share similar surface markers or ex vivo culturing characteristics [13]. However, in a large body of literature, the term EPC is still tacitly used to refer to angiogenic cells–whether from the endothelial lineage or not–that facilitate the generation of endothelium via either direct differentiation or various other mechanisms [14]. So far, several nomenclature methods have been proposed to solve this problem [15]. Although we acknowledge the need for more systematic categorizing systems, and will use them for reference repeatedly, we do not avoid referring to the whole population of those cells as EPCs in order to be consistent with past research and to steer clear of further unnecessary confusions.

Origins and differentiation

Initially believed to be a homogenous class of cells mobilized from the bone-marrow to promote endothelialization, EPCs have recently been suggested to be a miscellany of cells instead that have different origins and reside in various sites, such as the spleen, vascular adventitia and even the endothelium itself [16,17]. Depending on their origins, EPCs might differ in their roles in angiogenesis and proliferation potentials [18]. Nonetheless, the majority of what we now refer to as EPCs in the circulation is still believed to be directly derived from the bone marrow. Most EPCs in the bone marrow reside in structures called stem cell niches’ where they undergo differentiation [19]–a process that is accompanied by a series of changes in cellular surface markers. The common precursors of EPCs–progenitor cells that are characterized by the expression of CD133, a surface marker for immature human stem cells [20]–give rise to at least three cell lineages: the endothelial, monocytic and lymphocytic lineage. As those cells further differentiate, the expression of CD133 fades, and monocytic (CD14), lymphocytic (CD45) or haematopoietic/endothelial surface markers (CD34, VEGFR) gradually emerge [21]. The monocytic/lymphocytic lineage EPCs end up in what is currently referred to as ‘circulatory angiogenic cells’ (CACs), ‘early EPCs’ or ‘colony forming unit-endothelial cells (CFU-EC)’, whereas the descendants from the endothelial lineage eventually maturate into actual endothelial cells, and are referred to as ‘endothelial colony forming cells’ (ECFCs), ‘endothelial outgrowth cells’ (EOCs) or ‘late EPCs’ [15]. The distinct characteristics of each of those EPC subtypes will be discussed later.

Mobilization and homing

Under normal conditions, most of the bone marrow EPCs remain in close contact with bone marrow stromal cells and are relatively inactive. When stimulated by mobilization factors (e.g. SDF-1 and VEGF), a series of reactions (e.g. those involving nitric oxide, metalloproteinases, c-Kit and its receptors) take place, which weakens the connections between EPCs and stromal cells, and culminate in the release of EPCs from the bone marrow [22]. After entering the peripheral circulation, EPCs are recruited to sites where there is disruption of endothelial homoeostasis or active angiogenesis. This process is frequently termed as ‘EPC migration’ or ‘homing’. Several chemoattractants have been proven to be involved during EPC homing, such as SDF-1 and vascular endothelial growth factor (VEGF) [23,24]. Of note, bradykinin, a potent endothelium-dependent vasodilator produced by the kinin-kallikrein system also participates in the migration process via binding to B2 receptors on EPCs [25]. Once EPCs are localized, their incorporation into the endothelium is mediated by adhesion molecules in the integrin or selectin family [26].

Functions

There are two terms that have been frequently used to denote the process of blood vessel formation: ‘angiogenesis’ and ‘vasculogenesis’. Because of their similarity to each other, confusion over the correct use of terms are not uncommon. Whereas vasculogenesis refers to the de novo formation of vascular endothelium in non-vascularized tissues, angiogenesis indicates the development of vascular structures from existing vessels [27]. Although EPCs play important roles in both processes, much more emphasis has been placed on EPCs’ angiogenic properties in the realms of cardiovascular research. Therefore, by ‘EPC function’ in this review, we refer specifically to EPC's angiogenic abilities based upon pre-existing blood vessels.

It is now widely accepted that different subpopulations of EPCs function dissimilarly at sites of angiogenesis. CACs promote vascularization in a paracrine fashion–by releasing exosomes that contain a spectrum of angiogenic factors including SDF-1 and VEGF to enhance the activity of adjacent cells [15,28]. Endothelial lineage EPCs, on the other hand, have high proliferative capacities and tend to sustain endothelial integrity through direct incorporation [29]. More recent studies have unveiled several communication mechanisms that allow substances other than angiogenic cytokines (e.g. mRNA, lysosomes) to be directly transferred from EPCs to endothelial cells, such as secretion of microvesicles [30] and the formation of tunnelling microtubules [31].

Isolation and cultivation of EPCs

As has been discussed earlier, we now understand that the term ‘EPC’ as a definition is no longer deemed accurate. Nevertheless, some of the criteria initially used to characterize EPCs ex vivo still remain in use, which are the ability to facilitate endothelial formation, and the uptake of 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine-labelled acetylated low density lipoprotein (DiLDL) and lectin. Thus far, there are three generally accepted culturing methods to yield EPCs that meet those requirements.

Proposed by Kalka et al. in 2000, the first method involves isolating mononuclear cells from blood samples using density gradient centrifugation and then cultivating them on dishes coated with fibronectin and gelatin. Cells adherent to the media on day 4 of culture were identified as EPCs [32]. Those cells are commonly called ‘early EPCs’. They have short lifespans, usually die within 4 weeks in culture, and are thought to be representatives of monocytic lineage CACs which were described earlier.

A second method was soon introduced by Hill et al. [9], where certain modifications were made to the first method–adherent cells were removed after 48 h of culture, and non-adherent cells were re-plated on another dish coated by human fibronectin to finally obtain EPCs. Although the initial purpose of developing this method was to avoid contamination by non-EPCs, the cell colony formed in this method turned out to be a uniquely assorted set of cells–angiogenic T-lymphocytes at the centre of the colony, and early EPCs that surrounded them [33]. Those cells now tend to be referred to as CFU-ECs.

Researchers later discovered that, if mononuclear cells in the first method were cultivated for a prolonged period of time (usually >14 days), they acquire a set of cellular characteristics that are completely different from those obtained earlier in culture. They took on a cobble-stone appearance, were highly proliferative, and could form tube-like structures that resemble actual vascular endothelium. Different culture media have also been used to attain those cells [34]. Those ‘late’ EPCs are believed to be true endothelial precursors, and are sometimes referred to as ‘ECFCs’ or ‘endothelial outgrowth cells’ [15].

EPC quantification methods and function testing

Two types of methods have been used to quantify EPCs: flow cytometry and in vitro assays [35]. Although flow cytometry remains the most straightforward method to quantify circulatory EPCs, this technique suffers from a common limitation in stem cell research–the lack of exclusive surface markers to characterize given types of stem cells. The most frequently employed markers to identify EPCs are CD34 and kinase domain insert receptor (KDR), yet CD34 is a fairly generic haematopoietic progenitor cell marker, and KDR is almost ubiquitously expressed in vascular tissues. For this reason, some researchers have advocated the addition of CD133 to the gating protocol to sift out more immature stem cells, and the exclusion of CD45 to rule out cells that are not from the endothelial lineage. The quantification of EPCs in vitro involves measuring the colony formation ability of those cells. Unlike flow cytometry, which merely reflects the circulating levels of cells at a certain time point and gives no indication about their physiological status, quantification via in vitro methods is, in fact, an assessment of EPCs’ proliferating capability, which can be affected by cell senescence, and is often accompanied by declines in other cellular functions. Numerous ex vivo testing methods have been developed to evaluate different EPC functions, such as the expression of paracrine factors, migration and tube formation. However, most of those assays are originally designed for other cell types, and there is also a lack of standardized functional tests for EPCs. Because of this, many researchers have resorted to ischaemic animal models where more reliable measures of EPC angiogenic function (e.g. assessment of blood flow restoration at ischaemic sites after direct injection of EPCs) could be obtained.

EPC AND HYPERTENSION

EPC pathophysiology in hypertension: from observations to hypotheses

It was not until 4 years after the discovery of EPCs that the association between hypertension and EPC dysfunction was brought to our attention. In a study involving a cohort of 45 patients with coronary artery disease, Vasa et al. [8] suggested that a history of chronic hypertension was the most important independent predictor of EPC function impairments. Since then, numerous efforts have been made by researchers to examine the relationship between EPC and hypertensive disorders (particularly EH). It was then discovered that hypertension was also associated with alterations in the circulating levels, expression of genes and cellular life span of EPCs [9,10,36,37]. However, as data accumulated, conflicts also arose. For instance, although the number of EPCs from hypertensive patients were observed to be declining in many studies, some researchers failed to reproduce such results, and some even found increases in circulating EPC levels in patients with EH [36,38,39]. As our knowledge about EPCs expanded, it now became apparent that those inconsistencies were caused in large part by the heterogeneous nature of study designs in terms of study subjects, definition of hypertension and EPC quantifying methods, to name a few. Because of this, more caution has been taken to rigorously define those elements in the latest studies in this area of research.

Until now, findings from clinical observational studies on this subject have hinted at a fairly complex nature of the association between EPC and hypertension. Through summarizing data from all of those studies (as shown in Table 1), one can get a glimpse of several interesting patterns about the EPC–hypertension relationship. First, EPC functional decline seems to occur more commonly and, quite seemingly, earlier than reductions in EPC quantity in patients with EH [4043]. Second, both reductions in EPC count and EPC function can be restored by antihypertensive treatment [36,37]. Third, different types of EPCs may be affected differently in patients with EH–late EPCs undergo more significant declines in proliferative activity than other types of EPCs [44,45], and the number of circulating EPCs measured using flow cytometry appeared to be more subject to changes than EPCs quantified via in vitro methods. Fourth, endothelial dysfunction resulting from localized vascular injury can cause increases in EPC circulating numbers and enhancements of EPC biological functions [37,46], which was confirmed by evidence from experiments on mice [47]. It was also demonstrated that such response of EPCs to acute endothelial disruptions could be elicited in a rather swift manner [37], supporting the theory that neurohormonal mechanisms were involved in this process (which will be explained later). Finally, the quantitative and functional declines of EPCs become more pronounced in the advanced stages of hypertension (which can manifest as intractable high blood pressure, increased incidence of adverse vascular events and end organ damage) [39,44,4850].

Table 1
A summary of existing clinical observational studies on the relationship between EPC and hypertension

BP, blood pressure; BRB, β-receptor blockers; CAD, coronary heart disease; cEPC, circulating endothelial progenitor cell; DiLDL, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine-labelled acetylated low density lipoprotein; FMD, flow mediated dilation; HOXA9, Homeobox protein Hox-A9; NA, not available; NS, changes not significant; PWV, pulse wave velocity; vWF, von Willebrand factor. *Definition of refractory hypertension: failure of blood pressure control by triple-drug regimens and lifestyle modifications.

StudyFactor studied and patient/intervention characteristicsType of EPCEPC quantityEPC functionOther correlations
Vasa 2001 [8Hypertension (history > 1 year, receiving medical therapy) in the context of CAD cEPC (CD34+ KDR+) NS ↓ Migration ↓ EPC count with ↑ number of CAD risk factors 
  CAC (DiLDL+ lectin+) NS   
Hill 2003 [9Hypertension (as in Framingham risk score, antihypertensives discontinued for 2 weeks) CFU-EC (DiLDL+ CD31+ KDR+) ↓ ↑ Senescence ↓ EPC count with ↓ brachial FMD and ↑ Framingham risk score 
Imanishi 2005 [10Essential hypertension (treated with antihypertensives) CAC NA ↓ Telomerase activity;
↑ senescence 
↑ EPC senescence with ↑ hypertension severity index (reflects target organ damage) 
Delva 2007 [38Essential hypertension (antihypertensives discontinued for 1 month) CAC (DiLDL+ lectin+) NS NA ↑ EPC count with ↑ blood cholesterol 
 Essential hypertension (treated with ACEIs/BRBs/statins) CAC (DiLDL+ lectin+) NS NA  
Pirro 2007 [36Essential hypertension (never treated) cEPC (CD34+ KDR+) ↓ ↓ HOXA9 expression ↓ EPC count with ↑ Framingham risk score 
 Essential hypertension (treated with Ramipril) cEPC (CD34+ KDR+) ↑ ↑ HOXA9 expression  
Coppolino 2008 [37Essential hypertension (treated with antihypertensives) cEPC (CD34+ KDR+/CD133+ KDR+) NS ↑ Cell adhesion molecule expression ↑ EPC count and expression of surface molecules immediately after cold pressor test 
Oliveras 2008, 2009 [39,48Refractory hypertension* cEPC (CD34+ CD45+ CD133+) ↓ NA ↓ EPC count with ↓ brachial FMD 
 Refractory hypertension* CAC (DiLDL+ lectin+) ↓ NA  
Magen 2009 [49Essential hypertension (target BP control achieved) cEPC (CD34, 133, KDR dual positive) NS NA NA 
 Refractory hypertension* cEPC (CD34, 133, KDR dual positive) ↓ NA  
Giannotti 2010 [40Prehypertension (never treated) cEPC (CD34+ KDR+) NS ↓ Repair capacity, ↓ NO production, ↑ senescence ↓ EPC repair capacity with ↓ brachial FMD 
  CAC (DiLDL+ lectin+) NS   
 Essential hypertension (never treated) cEPC (CD34+ KDR+) NS ↓ Repair capacity, ↓ NO production, ↑ senescence  
  CAC (DiLDL+ lectin+) NS   
Yang 2010 [41Essential hypertension (never treated) cEPC (CD34+ KDR+) NS ↓ Proliferation and ↓ migration ↓ EPC proliferation and migration with ↑ arterial stiffness 
  CAC (DiLDL+ lectin+) NS   
Huang 2010 [44Essential hypertension (BP > 140/90 mmHg or treated with antihypertensives) with micro/macro albuminuria cEPC (CD34, 133, KDR dual positive) ↓ ↓ Proliferation;
↓ migration;
↑ senescence;
↑ apoptosis 
↓ EPC proliferation, migration,
↑ EPC senescence and
apoptosis with ↑ CD31+ annexin+ apoptotic microparticles in hypertensive patients with albuminuria 
  CFU-EC (DiLDL+ lectin+) ↓   
  ECFC (VE-cadherin+ CD31+ CD34+) ↓   
Lee 2011 [50Essential hypertension (BP > 140/90 mmHg or treated with antihypertensives) with left ventricular hypertrophy on electrocardiogram cEPC (CD34+ KDR+) ↓ ↓ Adhesion NA 
  CAC (lectin+) ↓   
MacEneaney 2011 [42Prehypertension (never treated) CFU-EC (DiLDL+ VE-cadherin+ CD31+ vWF+ KDR+) NS Preserved migratory capacity, no increase in apoptosis ↓ EPC count with ‘high prehypertension’ (systolic BP > 130 mmHg) 
Shantsila 2011 [46Essential hypertension (never treated) with history of retinopathic haemorrhagic events cEPC (CD34+ KDR+) ↑ NA History of retinopathic haemorrhagic events with ↑ PWV 
Bogdanski 2012 [101Grade 1–2 essential hypertension (never treated) with elevated plasma homocysteine CFU-EC (DiLDL+ lectin+) ↓ NA ↓ EPC count with ↑ carotid intima-media thickness 
Eirin 2013 [72Essential hypertension (treated with antihypertensives) in black people cEPC (CD34+ KDR+) ↓ NA ↓ EPC count with ↑ circulating inflammatory ECs and cytokines 
De Cavanagh 2014 [45Essential hypertension (target BP control achieved) CAC (DiLDL+ lectin+) ↓ ↓ Tunneling nanotube formation ↓ EPC count and ↓ tunneling nanotube formation with sympathetic nervous activity 
  ECFC (DiLDL+ lectin+) ↓   
StudyFactor studied and patient/intervention characteristicsType of EPCEPC quantityEPC functionOther correlations
Vasa 2001 [8Hypertension (history > 1 year, receiving medical therapy) in the context of CAD cEPC (CD34+ KDR+) NS ↓ Migration ↓ EPC count with ↑ number of CAD risk factors 
  CAC (DiLDL+ lectin+) NS   
Hill 2003 [9Hypertension (as in Framingham risk score, antihypertensives discontinued for 2 weeks) CFU-EC (DiLDL+ CD31+ KDR+) ↓ ↑ Senescence ↓ EPC count with ↓ brachial FMD and ↑ Framingham risk score 
Imanishi 2005 [10Essential hypertension (treated with antihypertensives) CAC NA ↓ Telomerase activity;
↑ senescence 
↑ EPC senescence with ↑ hypertension severity index (reflects target organ damage) 
Delva 2007 [38Essential hypertension (antihypertensives discontinued for 1 month) CAC (DiLDL+ lectin+) NS NA ↑ EPC count with ↑ blood cholesterol 
 Essential hypertension (treated with ACEIs/BRBs/statins) CAC (DiLDL+ lectin+) NS NA  
Pirro 2007 [36Essential hypertension (never treated) cEPC (CD34+ KDR+) ↓ ↓ HOXA9 expression ↓ EPC count with ↑ Framingham risk score 
 Essential hypertension (treated with Ramipril) cEPC (CD34+ KDR+) ↑ ↑ HOXA9 expression  
Coppolino 2008 [37Essential hypertension (treated with antihypertensives) cEPC (CD34+ KDR+/CD133+ KDR+) NS ↑ Cell adhesion molecule expression ↑ EPC count and expression of surface molecules immediately after cold pressor test 
Oliveras 2008, 2009 [39,48Refractory hypertension* cEPC (CD34+ CD45+ CD133+) ↓ NA ↓ EPC count with ↓ brachial FMD 
 Refractory hypertension* CAC (DiLDL+ lectin+) ↓ NA  
Magen 2009 [49Essential hypertension (target BP control achieved) cEPC (CD34, 133, KDR dual positive) NS NA NA 
 Refractory hypertension* cEPC (CD34, 133, KDR dual positive) ↓ NA  
Giannotti 2010 [40Prehypertension (never treated) cEPC (CD34+ KDR+) NS ↓ Repair capacity, ↓ NO production, ↑ senescence ↓ EPC repair capacity with ↓ brachial FMD 
  CAC (DiLDL+ lectin+) NS   
 Essential hypertension (never treated) cEPC (CD34+ KDR+) NS ↓ Repair capacity, ↓ NO production, ↑ senescence  
  CAC (DiLDL+ lectin+) NS   
Yang 2010 [41Essential hypertension (never treated) cEPC (CD34+ KDR+) NS ↓ Proliferation and ↓ migration ↓ EPC proliferation and migration with ↑ arterial stiffness 
  CAC (DiLDL+ lectin+) NS   
Huang 2010 [44Essential hypertension (BP > 140/90 mmHg or treated with antihypertensives) with micro/macro albuminuria cEPC (CD34, 133, KDR dual positive) ↓ ↓ Proliferation;
↓ migration;
↑ senescence;
↑ apoptosis 
↓ EPC proliferation, migration,
↑ EPC senescence and
apoptosis with ↑ CD31+ annexin+ apoptotic microparticles in hypertensive patients with albuminuria 
  CFU-EC (DiLDL+ lectin+) ↓   
  ECFC (VE-cadherin+ CD31+ CD34+) ↓   
Lee 2011 [50Essential hypertension (BP > 140/90 mmHg or treated with antihypertensives) with left ventricular hypertrophy on electrocardiogram cEPC (CD34+ KDR+) ↓ ↓ Adhesion NA 
  CAC (lectin+) ↓   
MacEneaney 2011 [42Prehypertension (never treated) CFU-EC (DiLDL+ VE-cadherin+ CD31+ vWF+ KDR+) NS Preserved migratory capacity, no increase in apoptosis ↓ EPC count with ‘high prehypertension’ (systolic BP > 130 mmHg) 
Shantsila 2011 [46Essential hypertension (never treated) with history of retinopathic haemorrhagic events cEPC (CD34+ KDR+) ↑ NA History of retinopathic haemorrhagic events with ↑ PWV 
Bogdanski 2012 [101Grade 1–2 essential hypertension (never treated) with elevated plasma homocysteine CFU-EC (DiLDL+ lectin+) ↓ NA ↓ EPC count with ↑ carotid intima-media thickness 
Eirin 2013 [72Essential hypertension (treated with antihypertensives) in black people cEPC (CD34+ KDR+) ↓ NA ↓ EPC count with ↑ circulating inflammatory ECs and cytokines 
De Cavanagh 2014 [45Essential hypertension (target BP control achieved) CAC (DiLDL+ lectin+) ↓ ↓ Tunneling nanotube formation ↓ EPC count and ↓ tunneling nanotube formation with sympathetic nervous activity 
  ECFC (DiLDL+ lectin+) ↓   

There are several possible explanations for these phenomena. In the early stages of hypertension, widespread endothelial dysfunction may serve as a stimulus for EPC mobilization, which accounts for the increases in circulating EPCs observed in some studies. However, in many cases, hypertensive subjects have inhibited bone marrow stem cell activity, which prevents further release of EPCs into the periphery [51]. As for the EPCs that nonetheless entered the circulation, they may only have a low proliferative capability and are subject to accelerated senescence under the influence of a combination of factors (which will be discussed in detail later). Those hypotheses together give an interpretation of the inconsistencies in circulating EPC count observed in patients with EH. As hypertension progresses, EPC dysfunction also becomes more pronounced. Nevertheless, circulating EPC levels might also be occasionally increased, possibly as a consequence of acute haemostatic stimuli. Eventually, the ‘EPC reserve’ reaches a point of depletion, where severe decline in EPC activity exacerbates endothelial dysregulation, leading to multiple end organ damage and greater chances of adverse cardiovascular outcomes.

Taken together, the relationship between EPC and hypertension needs to be recognized as a pathophysiological process far more complicated than a simple linear relationship, and emphasis should be placed on the different stages of hypertension, different EPC functions, and the relationships among different subtypes of EPCs in future research on this subject.

EPC dysregulation and essential hypertension: what is in between?

Despite the many significant findings from the aforementioned observational studies, the issue that lies at the heart of the present subject remains unresolved–EPC dysregulation and hypertension, which is the cause, which is the consequence and who are the accomplices?

To shed more light on this problem, researchers placed their hope on identifying and studying the ‘links’ that might have connected EPC and hypertension with each other. One of the most straightforward postulations is that EPC dysfunction was a consequence of the haemodynamic alterations caused by chronic elevations of blood pressure. Indeed, fluid biomechanical forces can affect the behaviour of vascular stem cells through a variety of mechanisms [52,53], and the alterations of physical forces within the blood flow almost certainly contributed to EPC dysfunction in patients with hypertension [54]. However, the correlation of blood pressure with either the quantity or the functions of EPCs turned out to be weak in many studies [36,38], which implies the presence of other mechanisms responsible for hypertension related EPC abnormalities.

To date, research into the pathogenesis of EH has been focusing on several areas including the autonomic nervous system (ANS) [55], the renin–angiotensin–aldosterone system (RAAS) [56], inflammation and the immune system [57]. All of those factors have also been shown to be intricately involved in EPC dysregulation (Figure 1).

A proposed model for the regulatory mechanisms that mediate the association between EPC dysfunction and hypertension

Figure 1
A proposed model for the regulatory mechanisms that mediate the association between EPC dysfunction and hypertension
Figure 1
A proposed model for the regulatory mechanisms that mediate the association between EPC dysfunction and hypertension

EPC and the autonomic nervous system

Both direct and indirect evidence have pointed to the involvement of ANS in the altered EPC behaviour in hypertensive subjects. The mobilization of EPCs can take place within minutes under acute vascular stress caused by external stimuli, such as cold temperature [37]. Since there was no actual damage to the endothelium in those circumstances, a fast response is quite likely to have been achieved via neurohormonal mechanisms. It was not until several years later, however, that clues about the mechanisms of neurohormonal regulation on EPC activity began to surface. Under physiologic conditions, the balance of stem cell activity is partly maintained by the circadian alternations of sympathetic and parasympathetic outflow from ANS regions of the brain [e.g. nucleus of the solitary tract (NTS), paraventricular nucleus and the rostral ventrolateral medulla (RVLM)] to the bone marrow [58]. In subjects with hypertension, however, the ANS sympathetic drive becomes persistently elevated, which inhibits EPC differentiation and their release from the bone marrow, leading to significant drops in circulating EPC levels [59]. Apart from this, the ANS also has other effects on EPCs. It was discovered by Galasso et al. [60] that β-adrenoreceptors existed on the surface of rat EPCs, and the activation of those receptors could enhance cell proliferation, migration and angiogenesis. A study by De Cavanagh et al. [45] later demonstrated that different adrenergic transmitters have distinct effects on cellular functions in different subtypes of EPCs. Interestingly, it is also reported that late EPCs express nicotinic acetylcholine receptors, whose activation leads to enhanced EPC activity [61]. Although it is reasonable to think that those receptors are related to the effects of tobacco smoking on EPCs [62], whether those receptors also take part in the association between EPCs and hypertension has yet to be determined. In conclusion, the ANS may facilitate responses of EPCs to noxious endothelial stimuli in normal conditions, but an abnormally high sympathetic outflow that is often present in chronic hypertensive subjects can cause undesirable pathophysiologic alterations of EPCs.

EPC and the renin–angiotensin–aldosterone system

It is now generally accepted that the RAAS mediates the detrimental effects of many risk factors on the cardiovascular system. In various cells within the vasculature (e.g. endothelial cells and vascular smooth muscle cells), angiotensin II (Ang II)–a major component of the RAAS–enhances the production of oxidative stress after binding to angiotensin receptors (AT1Rs), thereby altering a spectrum of cellular activities that lead to unfavourable pathologic processes, such as vascular remodelling and increased risks of adverse cardiovascular outcomes [63]. Aldosterone, another downstream effector of the RAAS, is also associated with elevated cardiovascular risks that are independent of its blood pressure raising effects [64]. Recently, evidence has suggested an intricate interplay among EPCs with various components of the RAAS. First, a series of studies were done to assess EPC biology in a special cohort of subjects–patients with Bartter/Gitelman syndrome (BS/GS). BS and GS are a set of hereditary diseases characterized by endogenously blunted Ang II signalling, and are considered a unique human disease model to study the relationship between RAAS and EPCs because they provide confounder-free ‘mirror images’ of the effects that Ang II has on EPCs [65]. In patients with BS/GS, the circulating number of CD133+ EPCs was observed to be increased, which was assumed to be a result of alterations in pathways that involve haem-oxygenases, calcitonin gene-related peptides and nitric oxide (NO) [66,67]. However, there was no observable changes in CD34+ KDR+ cells in those patients [67], suggesting not all types of EPCs are controlled by the RAAS. Aside from those studies, it was soon revealed that EPCs express both angiotensin and aldosterone receptors, and once activated, these receptors trigger a cascade of downstream reactions that mainly involve imbalances in reactive oxygen species (ROS) and NO syntheses (which will be described in detail later) finally resulting in EPC dysfunction and shortening of cellular life span [68,69]. Other studies have indicated that abnormal RAAS activity in hypertensive patients contributed to EPC dysfunction by acting on the cardiovascular regions in the central nervous system (CNS). Although AT1Rs can be found on many neurons within the CNS, their role in regulating CNS control on bone marrow EPC activity and blood pressure may be multifaceted. The expression of AT1R in the nucleus of solitary tract was down-regulated in hypertensive rats, and this was found to be correlated with a decline in circulating EPC numbers [70]. However, in other sites of the brain such as the paraventricular nucleus, chronic elevations in Ang II inhibit neuron firing through ROS generation, eventually causing decreases of EPCs in the bone marrow [71]. Of note, EPCs might also be influenced indirectly by the RAAS. For instance, an increased activity of angiotensin converting enzyme (ACE) may hinder EPC migration through accelerating the degradation of bradykinin, which was proven to be an EPC chemotactic factor [25]. This evidence taken together hints at a very interesting web of interactions among hypertension, the RAAS, and EPCs.

EPC and inflammation

Because certain subpopulations of EPCs are technically immune cells themselves (CACs originate from the monocytic lineage, and CFU-ECs include angiogenic T-cells), the physiology of EPCs is without doubt closely related to the immune system. However, research into the pathogenetic roles of inflammation and the immune system in hypertension has just begun to gather momentum in the past few years. So far, researchers have been able to identify certain correlations between inflammatory biomarkers and EPCs. Eirin et al. [72] revealed that the number of inflammatory endothelial cells–cells that have detached from sites of endothelial inflammation–were associated with circulating levels of EPCs in patients with EH [73], and those cells, quite possibly, contributed to EPC dysfunction. Negative associations of EPC function with a series of inflammatory cytokines, such as IFN-γ and TNF-α, have also been demonstrated in patients with EH [74], which might be explained by the interactions between EPCs and macrophages. Evidence has shown that EPCs were able to interact with macrophages, shifting them towards less inflammation-prone phenotypes, thereby decreasing the levels of cytokines and inhibiting inflammation [75]. Aside from inflammatory cells and cytokines, another potential inflammatory regulator of EPC physiology is endothelial microparticles (EMPs) [76]. These particles are complex fragments shed from endothelial cells that are undergoing apoptosis or activated by various stimuli such as inflammation [77]. They have been found to be increased in patients with EH [44]. Since the functions of EMPs are multifaceted–they can aggravate inflammation, promote coagulation and regulate vascular endothelial homoeostasis in various ways [78]–further research into the interrelations among the endothelium, EMPs and EPCs in patients with EH might yield very appealing findings.

The bigger picture

The intricate interplay among the ANS, the RAAS, the immune system and the haemodynamics of the circulatory system forms a complicated pathophysiologic network in patients with EH, and each of those elements play a significant role regulating EPC cellular biology. The main stem of this network arises from what we may call ‘the brain-bone marrow-periphery axis’: Central cardiovascular ANS outflow regulates the activity of numerous stem cells in the bone marrow, resulting in altered numbers of not only EPCs but various inflammatory cells in the peripheral circulation, thereby contributing to immune dysregulation and persistent endothelial inflammation in end organ vasculatures [59]. The RAAS, on the other hand, has several interactions with this axis. Ang II induces hypertension, inflammation and EPC dysfunction via acting on central ANS neurons [71], aldosterone inhibits bone marrow EPCs in their early stages of differentiation [79], and both Ang II and aldosterone can alter angiogenic functions by directly acting on receptors expressed by EPCs.

After all that has been discussed, we now have an answer to the question in the very beginning of this section–instead of being causal to one another, chronic elevations in systemic blood pressure, endothelial dysfunction and abnormalities in EPC biology may all be the consequence of a combination of complex regulatory mechanisms and pathophysiologic processes (Figure 2).

The involvement of the CNS, the RAAS and inflammation in EPC pathophysiology

Figure 2
The involvement of the CNS, the RAAS and inflammation in EPC pathophysiology

B2R, bradykinin receptor B2; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; MMP-9, matrix metallopeptidase 9; PSGL-1, P-selectin glycoprotein ligand 1; PVN, paraventricular nucleus of the hypothalamus.

Figure 2
The involvement of the CNS, the RAAS and inflammation in EPC pathophysiology

B2R, bradykinin receptor B2; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; MMP-9, matrix metallopeptidase 9; PSGL-1, P-selectin glycoprotein ligand 1; PVN, paraventricular nucleus of the hypothalamus.

Molecular pathways associated with EPC pathophysiology in hypertension

It is a disappointing fact that, so far, there have only been a handful of studies attempting to unravel the signalling pathways that associate EPC dysfunction with systemic hypertension [60,68,8085], leaving the molecular mechanisms behind the alterations in EPC biology largely inconclusive. Nevertheless, the limited evidence provides us with valuable information about certain distinctive features of EPCs. Possibly due to the presumption that late EPCs are phenotypically much more similar to mature endothelial cells, most studies on EPC molecular pathways have been performed on early EPCs. So far, receptors on those cells identified to be closely related to hypertension include endothelin receptors, AT1R, β2-adrenergic receptors and mineralocorticoid receptors (MR). These receptors, when activated, trigger a variety of reactions that mainly involve NADPH oxidases and antioxidant enzymes, leading to the generation of a common downstream effector, ROS. The accumulation of ROS promotes cell senescence, apoptosis and many other detrimental effects in EPCs via numerous mechanisms [86]. NO, one of the major second messengers in EPCs, is down-regulated by ROS via the uncoupling of tetrahydrobiopterin from endothelial NO synthases (eNOS) [87], and it appears that NO is an essential mediator of various EPC functions. For instance, when bound to ligands, KDR and β2-receptors activate the PI3K/Akt/eNOS pathway, thereby increasing the synthesis of NO, which eventually enhances the migration, proliferation and angiogenesis of EPCs. Those enhancements of cellular functions are achieved, in part, by up-regulations in the expression of several angiogenic factors as well as their receptors. The binding of those ligands and receptors mediates the chemotaxis of EPCs to sites of endothelial disruption, and also forms a positive feedback loop of angiogenesis by further bolstering the angiogenic functions of EPCs and prolonging their cellular life span via pathways such as the Jak-2 [81], p38 mitogen-activated protein kinases (p38 MAPK) [80] and PI3K/Akt pathways [60]. A graphic summary of all those pathways and how they are affected in subjects with hypertension is presented in Figure 3. It needs to be noted that all the discussions in this section are about early EPCs only. Other subtypes of EPCs may have distinct pathophysiologic characteristics, and complicated interactions may exist among different cells. However, up till now evidence of the molecular mechanisms underlying the relationships of those other types of EPCs with hypertension is scant, and further investigation is warranted.

A schematic of all known molecular pathways involved in hypertension-related early EPC dysregulation

Figure 3
A schematic of all known molecular pathways involved in hypertension-related early EPC dysregulation

β2-R, β2-adrenoceptor; ET-1, endothelin 1; ETaR, endothelin receptor type A; JAK-2, Janus kinase 2; NOX, NADPH oxidase; PKA, protein kinase A.

Figure 3
A schematic of all known molecular pathways involved in hypertension-related early EPC dysregulation

β2-R, β2-adrenoceptor; ET-1, endothelin 1; ETaR, endothelin receptor type A; JAK-2, Janus kinase 2; NOX, NADPH oxidase; PKA, protein kinase A.

CLINICAL IMPLICATIONS

Diagnostics

Since hypertension is an important risk factor for many cardiovascular diseases, risk stratification and prevention have always been at the centre of the clinical management of hypertension. Given the crucial role of the endothelium in the pathogenesis of various cardiovascular diseases, many assays have been developed to predict cardiovascular outcome and hypertension end organ damage via assessment of endothelial function. However, because the endothelium is relatively inaccessible to direct examination, the most reliable parameters of endothelial function have to be acquired using invasive methods which are costly and laborious [88]. For many non-invasive endothelial function tests, their predictive values are controversial, and the testing procedures can be quite time-consuming and unpleasant for patients. Therefore, researchers have sought to develop surrogate indicators of endothelial function that are less costly, more accessible, and sufficiently accurate in predicting cardiovascular risk. Currently, EPCs are considered a promising marker of such kind, giving consideration to their close relationship with the endothelium, and their accessibility (they can be obtained via a single collection of venous blood sample). The predictive value of circulating EPC levels has been confirmed in many studies [6,7,89], and in certain cases, they may even turn out to be more prognosticative than traditional endothelial function tests [9]. Although the potential of EPCs being used as a clinical biomarker is still limited by the lack of standard quantifying and isolation protocol, it needs to be acknowledged that EPCs are actually a functionally coordinated group of angiogenic cells that are related to multiple physiologic systems. In light of this, quantitative and functional parameters of different types of EPCs might be able to provide more information when interpreted along with other biomarkers. Indeed, EPC count has been shown to work well with other disease risk parameters. For example, the EPC-endothelial apoptotic microparticle ratio can be used to predict risk of hypertensive end organ damage [90], and the addition of blood EPC count increases the prognosticative values of risk stratification models consisting of traditional risk predictors [91].

Existing antihypertensive medications: reviewed from the EPC's perspective

The results from many clinical trials have indicated that regardless of specific classes of medications, it is the control of blood pressure that is essential to the reduction of cardiovascular risks in patients treated with antihypertensive agents [92]. However, concerns often arise when it comes to administering antihypertensive medications to specific individuals, and it is not always the more, the better. If you take RAAS antagonists as an example, the determinants of RAAS blocker response and the optimal degree of RAAS blockade in patients with hypertension have long been a topic of debate [56]. Moreover, the short-term and long-term response of an individual to specific antihypertensive medications can never be predicted with full certainty.

Since the discovery of EPCs, researchers have been enthusiastic about the influence that various medications have on those cells, and interestingly, many antihypertensives have been proven to have blood pressure independent beneficial effects on EPCs. So far, RAAS antagonists appear to be the most important class of medication to ameliorate EPC dysregulation associated with hypertension. Antagonists of nearly every component of the RAAS–direct renin inhibitors [93], angiotensin converting enzyme inhibitors (ACEIs) [94], angiotensin receptor blockers (ARBs) [95] and MR blockers [84]–have been proven to be able to either increase EPC circulating numbers or salvage them from functional decline. More interestingly, different mechanisms of action or different specificities for EPC subtypes have been suggested even for medications that are within the same class. Take, for instance, ARBs, where Calo et al. [96] discovered that olmesartan increases circulating EPC levels and decelerates EPC apoptosis possibly via mechanisms involving haem-oxygenases and calcitonin gene-related peptides. Honda et al. [97] also similarly suggested that telmisartan promotes early EPC proliferation by activation of the ‘PPARγ-dependent PI3K/Akt pathway’, whereas Yao et al. [98] demonstrated that losartan enhanced EPC migration and colony formation through down-regulating the expression of oxidases. Another major class of cardiovascular medicine found to have positive effects on EPCs are calcium channel blockers (CCBs). Whereas some CCBs may have antioxidant effects on EPCs similar to those of certain RAAS blockers [99], other types of CCBs (e.g. lacidipine and lercanidipine) seem to have their own distinct actions on the CXCR4/CXCR7 related pathways [80,81]. Studies have also revealed that some β-blockers (e.g. celiprolol) improve EPC migration and proliferation abilities, whereas others (e.g. atenolol) have no such effect [100], further supporting the theory that the influence of many antihypertensive agents on EPCs is dependent on the given agent's distinctive pharmacologic properties rather than their blood pressure controlling effects.

In summary, many medications have their own specific effects on various pharmacologic targets within EPCs, and further study into their mechanisms of action may lead to better understandings about EPC biology. In the future, novel biomarkers based on EPCs may be developed to provide guide for medical therapy in patients with hypertension.

CONCLUSION AND PERSPECTIVES

Hypertension is one of the most prevalent diseases worldwide. Patients with hypertension stand greater risks for damage to multiple organs and severe adverse cardiovascular events. Despite extensive research into the pathogenesis of EH, the exact mechanisms of its development have never been fully understood. Since the discovery of EPCs, many efforts have been made to study the relationship between hypertension and those cells, and it now gradually becomes clear that different types of EPCs undergo dissimilar changes in various stages of hypertension. Underlying those phenomena is a complex network of mechanisms that involve the ANS, the RAAS, the immune system and the signalling pathways associated with their effects on EPCs. Through studying those mechanisms, we will be able to better estimate the potential of EPCs being used to predict cardiovascular risk, or to guide medical therapy in patients with hypertension. Nevertheless, several hurdles remain in the way of advancement in this field of research, such as the need for more accurate categorization methods for EPCs and the lack of understanding about the actual mechanisms of EPCs’ interactions with the endothelium. To tackle these problems, further research is needed to improve the isolation methods of different subtypes of EPCs and to reveal the interrelations between them and various other cells such as endothelial cells and immune cells.

We thank Dr Rhian Touyz for inviting us to write this review article, and Mr. Zeen Li for technical support in editing the figures. Dr Shengyuan Luo is currently at the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA, which is where the final revisions of this article were made.

FUNDING

This work is supported by the 973 Program (2013CB531200); and the National Nature Science Foundation of China [grant numbers 31530023, and 31370941].

Abbreviations

     
  • ACE

    angiotensin converting enzyme

  •  
  • ACEI

    angiotensin converting enzyme inhibitor

  •  
  • Ang II

    angiotensin II

  •  
  • ANS

    autonomic nervous system

  •  
  • ARB

    angiotensin receptor blocker

  •  
  • AT1R

    angiotensin II receptor type 1

  •  
  • CAC

    circulating angiogenic cell

  •  
  • CCB

    calcium channel blocker

  •  
  • CD

    cluster of differentiation

  •  
  • CFU-EC

    colony forming unit-endothelial cell

  •  
  • CNS

    central nervous system

  •  
  • ECFC

    endothelial colony forming cell

  •  
  • EH

    essential hypertension

  •  
  • EMP

    endothelial microparticle

  •  
  • eNOS

    endothelial nitric oxide synthase

  •  
  • EPC

    endothelial progenitor cell

  •  
  • IFN

    interferon

  •  
  • KDR

    kinase domain insert receptor

  •  
  • MR

    mineralocorticoid receptor

  •  
  • NO

    nitric oxide

  •  
  • NTS

    nucleus of the solitary tract

  •  
  • p38 MAPK

    p38 mitogen-activated protein kinases

  •  
  • RAAS

    renin–angiotensin–aldosterone system

  •  
  • ROS

    reactive oxygen species

  •  
  • RVLM

    rostral ventrolateral medulla

  •  
  • SDF

    stromal cell derived factor

  •  
  • TNF

    tumour necrosis factor

  •  
  • VEGF

    vascular endothelial growth factor

  •  
  • VEGFR

    vascular endothelial growth factor receptor

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Author notes

1These authors contributed equally to this work.