The incidence of stroke and myocardial infarction increases in aged patients and it is associated with an adverse outcome. Considering the aging population and the increasing incidence of cardiovascular disease, the prediction for population well-being and health economics is daunting. Accordingly, there is an unmet need to focus on fundamental processes underlying vascular aging. A better understanding of the pathways leading to arterial aging may contribute to design mechanism-based therapeutic approaches to prevent or attenuate features of vascular senescence. In the present review, we discuss advances in the pathophysiology of age-related vascular dysfunction including nitric oxide signalling, dysregulation of oxidant/inflammatory genes, epigenetic modifications and mechanisms of vascular calcification as well as insights into vascular repair. Such an overview highlights attractive molecular targets for the prevention of age-driven vascular disease.

AGING AND CARDIOVASCULAR DISEASE

Aging is the main risk factor and driver of incident cardiovascular disease (CVD) and results in a progressive functional and structural decline of the vasculature [1]. Arterial aging, through its impact on physical and mental health, impairs quality of life and the ability of individuals to carry out the tasks of everyday life [2]. As the average lifespan of the European population is increasing, the overall future CVD burden in Europe is predicted to increase dramatically leading to a pandemic of frailty syndromes, poor quality of life and high morbidity in the aging population [3,4]. Since half of all people aged 65 years and older develop CVD, arterial aging has a profound impact on the health of populations in Europe [5,6]. Moreover, clustering of chronological age with other cardiovascular (CV) risk factors clearly anticipates senescent features of heart and vessels [7]. Intricate signalling cascades are emerging as determinants of accelerated arterial aging in the presence of CV risk factors. Accordingly, there is an unmet need to focus on fundamental processes of vascular aging enabling early diagnosis and prevention of CVD. This is important in the context that, although aging is inevitable, vascular aging is a modifiable risk factor.

STRUCTURAL ABNORMALITIES OF ARTERIAL AGING

Clinical and pre-clinical data have shown that aging is associated with structural and functional properties of large arteries [8]. Aging blood vessels become thicker and stiffer, resulting in a reduced ability to adjust vessel shape and function to changing tissue demands. In aged healthy humans, these alterations are represented by luminal dilation, increased arterial stiffness, endothelial dysfunction and diffuse intimal thickening. A decrease in vascular plasticity may be the result of different factors including enhanced elastin degradation and collagen deposition in the vascular media [9]. Importantly, remodelling of the vasculature is accompanied by key alterations of endothelial homoeostasis [10]. Indeed, seminal studies have clearly shown that endothelium-dependent vasorelaxation is impaired in aged vessels and this phenomenon is associated with increased vascular permeability and inflammation, as well as impaired angiogenesis [1,11]. Moreover, age-related alterations of endothelial cell functionality may, in turn, aggravate media thickness and vascular fibrosis.

NITRIC OXIDE SIGNALLING

Vascular aging, characterized by endothelial dysfunction and increased vascular stiffness, is associated with reduced endothelial nitric oxide (NO) bioavailability and increased generation of reactive oxygen species (ROS) [12]. Increased ROS production in vascular aging derives from enzymatic and non-enzymatic sources such as mitochondria [13]. Interestingly enough, dysregulation of the endothelial nitric oxide synthase (eNOS), known as eNOS uncoupling, results in loss of endothelial NO generation and increased ROS production [14]. The mechanism of eNOS-uncoupling seems multiple and includes oxidation of the cofactor tetrahydrobiopterin (BH4), decreased intracellular availability of the substrate L-arginine due to either increased arginase activity or accumulation of endogenous arginine analogues such as asymmetric dimethyl-L-arginine that competes with L-arginine for eNOS binding [15].

Tetrahydrobiopterin

The small molecule BH4 is a redox cofactor for eNOS and a pivotal regulator of its catalytic activity [14]. Loss of BH4 is associated with vascular disease states, including aging, and results in eNOS uncoupling reduced NO release and superoxide anion (O2) generation, in turn, leading to production of hydrogen peroxide and peroxynitrite (ONOO) (Figure 1) [12]. The role of BH4 in vascular aging has been demonstrated by several studies over the last 10 years. Older animals have reduced vascular BH4 levels due to its oxidation into dihydrobiopterin (BH2), which is not acting as a cofactor for eNOS. Such a shortage of cofactor leads to a conformational change in eNOS from a dimeric to monomeric state resulting in loss of NO production and ROS generation [15]. Pharmacological supplementation of BH4 can improve endothelial function in aged humans compared with young subjects [16], suggesting that BH4 treatment might be a rational approach to improve vascular function in aging [17].

Schematic representation of molecular pathways involved in arterial aging

Figure 1
Schematic representation of molecular pathways involved in arterial aging

VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intercellular adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1; MnSOD, manganese superoxide dismutase; ecSOD, extracellular superoxide dismutase.

Figure 1
Schematic representation of molecular pathways involved in arterial aging

VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intercellular adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1; MnSOD, manganese superoxide dismutase; ecSOD, extracellular superoxide dismutase.

Arginase II

L-Arginine, a major eNOS substrate, is rapidly metabolized by arginase enzyme to urea and L-ornithine, leading to a decrease in its availability and, hence, reduced NO synthesis [18]. An increasing body of evidence suggests that arginase II (Arg II) is deregulated in aging and participates to early vascular senescence by altering the phenotype of endothelial cells and vascular smooth muscle cells (VSMCs). A recent study performed in VSMCs isolated from human umbilical veins showed that Arg II overexpression activates p66Shc/p53 signalling, thus triggering mitochondrial dysfunction and cell apoptosis, key features of cellular aging. Consistently, gene silencing of Arg II attenuates senescence of human endothelial cells by maintaining a detrimental vicious cycle involving the mammalian target of rapamycin complex 1 (mTORC1)/S6 kinase (S6K1) pathway.

Activation of Arg II may represent an important link between CV risk factors and the aging process. Indeed, several common risk factors such as hyperglycaemia, hyperlipidaemia and obesity have been shown to increase Arg II expression/activity. Genetic deletion of Arg II reduces vascular inflammation in mice fed on a high-cholesterol and high-fat diet, prevents atherosclerosis and ameliorates insulin sensitivity as well as glucose homoeostasis [19,20]. These findings shed light on the role of Arg II as a common determinant across the spectrum of metabolic disease, atherosclerosis and senescence. The clinical impact of this gene is supported by the notion that arginase inhibition improves brachial artery vasodilation in subjects with Type 2 diabetes [21]. Pharmacological suppression of arginase activity may indeed restore physiological substrate levels, thus suppressing molecular pathways involved in endothelial aging and dysfunction (Figure 1).

Endothelial nitric oxide synthase

Alteration of eNOS transcription may be involved in age-related endothelial dysfunction but its biological significance remains unclear. Some studies found increased eNOS expression in aging and such observations have been interpreted as a compensatory but futile mechanism to counter-regulate the loss of NO [2,22]. In contrast, other work in humans and rodents did not show significant changes in eNOS expression but rather an increase or decrease in its activating Ser1177 phosphorylation [15,23,24]. Age-dependent impairment of NO release also plays an important role in the coronary circulation [25]. Indeed, eNOS deregulation is critically involved in microvascular dysfunction and impaired ventricular contractility in aged patients [26]. Moreover, advanced age is associated with less collaterals to the infarct-related artery in patients with acute myocardial infarction [27]. This abnormality may contribute to the poor prognosis of older patients with acute coronary syndromes. Collectively, these evidence strongly suggest that modulation of eNOS functionality is a promising target for prevention of age-related vascular disease.

OXIDATIVE STRESS

A major feature of CV aging is the imbalance between NO bioavailability and accumulation of ROS, leading to endothelial dysfunction [28]. Indeed, age-dependent generation of O2 inactivates NO to form ONOO, a powerful oxidant that easily penetrates across phospholipid membranes leading to substrate nitration [22,29]. Protein nitrosylation blunts activity of antioxidant enzymes and eNOS [30]. Generation of ROS into the vessel wall has been postulated as a major pathophysiological step favouring arterial aging [1,11]. Among the different aging theories, the mitochondrial free radical theory has been in the spotlight for several decades [31]. Accordingly, ROS are considered to be by-products of aerobic metabolism that induce oxidative cellular damage [32]. ROS, small highly reactive molecules, are generated within the cell by means of several metabolic and enzymatic pathways. The majority of ROS are produced within mitochondrial oxidative phosphorylation. During this process, electrons are extracted from NADH and FADH and transferred to molecular oxygen through a chain of four enzymatic complexes ensuring phosphorylation of ADP into ATP and final reduction of molecular oxygen to water. However, electrons derived from NADH or FADH can directly react with oxygen or other electron acceptors within the mitochondrial electron transport chain upstream the last enzymatic complex (complex IV, which is responsible for the reduction of molecular oxygen to water) and generate free radicals [33]. Accumulation of ROS causes mitochondrial disruption leading to cytochrome c release and subsequent activation of caspase 3 [1,33]. CV risk factors such as hyperglycaemia induce a ROS-dependent alteration of the mitochondrial network resembling early signs of vascular aging [28]. Indeed, endothelial cells isolated from middle-age diabetic subjects show a premature derangement of organelle structure, which correlates with impaired flow-mediated vasodilation of the brachial artery [34].

NAPDH oxidase

NADPH oxidases of the Nox family are differentially expressed in the CV system and may critically contribute to oxidative burden and vascular disease [35]. The NOX family consists of seven members: the classic NOXs, NOX1–NOX5, and the dual oxidases Duox1 and Duox2 [36,37]. A significant expression in the CV system has been reported for Nox1, Nox2, Nox4 and Nox5 [37]. As a consequence of the interaction between the different ROS-generating systems such as mitochondria and eNOS, NADPH oxidases have been demonstrated to contribute to ROS formation for almost all risk factor conditions. However, the contribution of NADPH oxidase in aging remains incompletely understood. This is likely to be due to the fact that the role of NADPH in cellular senescence has been overlooked, since the overproduction of ROS associated with aging has mainly been attributed to leakiness of the mitochondrial respiratory chain. Indeed, most of the available studies suggest that arterial aging is rather the result of impaired antioxidant enzyme expression, eNOS uncoupling, or increased ROS production by mitochondria [1]. However, few studies support a putative involvement of NOXs in arterial aging. A study has demonstrated that silencing of NOX4 in human endothelial cells leads to delayed replicative senescence and preserves cell functionality [38]. In line with these findings, we have recently shown that Nox2 and Nox4 are significantly up-regulated in the vasculature of aged mice, as well as only Nox2 increases in peripheral blood monocytes isolated from older individuals [39]. Furthermore, NADPH oxidase is a key mediator of endothelin-1-induced vasoconstriction, as well as cerebrovascular damage in aged rodents [40,41]. In contrast, a previous study showed that activation of NADPH subunits p47phox and p67phox remain unchanged in aged endothelial cells, suggesting that age-related oxidative stress mechanistically differs from endothelial dysfunction seen in the context of other CV risk factors [42]. Taken together, these results suggest that further research is needed to better understand the role of NADPH oxidase in arterial aging.

Activated protein-1 transcription factor JunD

Recently, the activated protein-1 (AP-1) transcription factor JunD has emerging as an important modulator of age-driven mitochondrial oxidative stress [43]. AP-1 is a collection of dimeric complexes made by different members of three families of DNA-binding proteins: Jun, Fos and activating transcription factor (ATF)/cAMP-response-element-binding protein-binding protein (CREB) [44]. These members assemble to form AP-1 transcription factors with activities that are strongly influenced by their specific components and their cellular environment. JunD, the most recent gene of the Jun family, regulates cell growth and survival and protects against oxidative stress by modulating genes involved in antioxidant defence and ROS production [45]. Our recent work has shown that JunD is a longevity gene implicated in the preservation of vascular homoeostasis during life [39] (Figure 1). We found that JunD is down-regulated by aging both in mouse aorta and peripheral blood monocytes of old as compared with young healthy individuals. Interestingly, age-dependent reduction in JunD expression was explained by a specific epigenetic signature, namely reduced methylation of CpG dinucleotides on the JunD promoter [39]. This latter finding strengths the notion that epigenetic signatures may critically participate in early phenotypes of vascular disease during the lifetime [46,47]. In our study, young JunD−/− mice showed early endothelial dysfunction and vascular senescence, which were comparable with the one observed in aged wild-type (WT) mice. JunD deletion was indeed associated with up-regulation of the aging markers p53 and p16INK4a, reduced telomerase activity and mitochondrial DNA damage [39]. Interestingly enough, transient overexpression of JunD was able to rescue endothelial dysfunction in aged mice. Mechanistically, we found that JunD is required for the expression of mitochondrial antioxidant enzymes such as manganese superoxide dismutase (MnSOD) and aldehyde dehydrogenase 2 (ALDH-2). This latter enzyme was almost abolished in young JunD−/− mice compared with age-matched littermates. The relevance of this finding is supported by the notion that ALDH-2 protects against ischaemia/reperfusion injury [48] and cardiac arrhythmias [49]. Moreover, JunD participates to eNOS transcription, thus contributing to preserve NO availability during aging [50]. The transcription factor also modulates the expression and activity of NADPH oxidase in the vasculature [39]. Indeed, JunD−/− mice display a premature up-regulation of the NADPH isoforms p47phox, Nox2 and Nox4 leading to increased vascular oxidative stress already in early stages of life. Moreover, in our study JunD expression negatively correlated with NADPH subunits in aged individuals. In line with our findings, lack of JunD promotes pressure-overload-induced apoptosis, hypertrophic growth and angiogenesis in the heart [51]. Collectively, these findings indicate that JunD down-regulation may represent a common molecular event linking premature senescence with CVD development.

Mitochondrial adaptor p66Shc

The identification of molecular pathways modulating the endothelial cell redox state is crucial in understanding the mechanisms linking vascular aging to endothelial dysfunction and atherosclerosis. In view of its role on the cellular redox state, mitochondrial p66Shc adaptor protein has been regarded as part of a putative transduction pathway relevant to endothelial integrity [11,52]. Intracellular free radicals are reduced in cells lacking the p66Shc gene (p66Shc−/− cells), and both systemic as well as intracellular free radicals are diminished in a p66Shc−/− mouse model exposed to high oxidative stress [53,54]. The p66Shc adaptor protein functions as a redox enzyme implicated in mitochondrial ROS generation and translation of oxidative signals into apoptosis (Figure 1) [53,5557]. Several chronic stimuli activate the protein kinase C βII (PKCβII) isoform to induce Ser36 phosphorylation of p66Shc, allowing transfer of the protein from the cytosol to the mitochondrion where it catalyses ROS production via cytochrome c oxidation [53]. This latter event leads to mitochondrial disruption and cell death. Indeed, increased ROS generation alters mitochondrial permeability facilitating the release of proapoptotic proteins such as cytochrome c [53]. Once into the cytosol, cytochrome c is responsible for activation of the apoptosis execution enzyme caspase-3. Accordingly, mice lacking the p66Shc gene (p66Shc−/−) display prolonged lifespan, increased resistance to oxidative stress and apoptosis. We have previously reported that endothelium-dependent relaxations in response to acetylcholine were age-dependently impaired in WT mice but not in p66Shc−/− mice [55]. Accordingly, p66Shc−/− mice were protected against the age-related decline in NO release. This study implies that p66Shc signalling is required to induce a ROS-driven vascular senescent phenotype. Importantly, p66Shc activation is thought to be upstream of the NADPH and mammalian target of rapamycin pathway, two important determinants of vascular damage [58]. Activation of p66Shc also promotes the heart senescent phenotype and development of heart failure in diabetic mice [59]. Accordingly, diabetic p66Shc−/− mice are protected against myocardial oxidative stress, apoptosis and telomere shortening. Despite these studies provided interesting insights into the role of p66Shc in CV aging, it remains unclear whether protein inhibition may reverse vascular disease phenotype. In this regard, we have demonstrated for the first time that in vivo RNA interference blunts vascular p66Shc expression, ROS generation and endothelial dysfunction in diabetic mice [60]. Moreover, experimental studies have recently shown that genetic deletion of p66Shc prevents age-related CV disease such as myocardial infarction and stroke [56,61]. Of interest, p66Shc expression is also affected by CV risk factors such as oxidized low-density lipoprotein and blood pressure [62,63]. These latter findings imply that the adaptor p66Shc may represent a critical molecular intermediate between CV risk factors and premature aging. The clinical relevance of p66Shc is supported by the notion that p66Shc gene expression is increased in mononuclear cells obtained from patients with Type 2 diabetes and coronary artery disease [64,65]. A study has shown that p66Shc expression is higher in fibroblasts isolated from centenarians [66]. This finding probably indicates that p66Shc expression may increase in a time-dependent manner. In contrast, early gene up-regulation due to risk factors may anticipate features of CV aging in middle-age individuals [64,67]. On the whole, the evidence reported so far supports the concept that modulation of p66Shc expression and activity may be a novel and effective approach for the treatment of age-related CVD.

INFLAMMATION

Inflammatory processes are known to contribute to age-related vascular disease, myocardial infarction, stroke and heart failure [32]. The molecular events underpinning age-dependent inflammation are not completely understood. Inflammatory alterations in aging include induction of cellular adhesion molecules, an increase in endothelial–leucocyte interactions and alterations in the secretion of autocrine/paracrine mediators, which are pivotal to inflammatory responses.

ROLE AND MOLECULAR TARGETS OF SIRTUINS IN THE AGED VASCULATURE

The family of nicotinamide adenine dinucleotide-dependent proteins termed sirtuins has recently emerged as an important regulator of arterial aging. SIRT1 is considered a major gatekeeper against oxidative stress and tissue inflammation [68]. Increased SIRT1 activity confers resistance to many of the CV sequelae associated with aging [69]. Activation of SIRT1 in endothelial tissues may be of benefit in preserving endothelial cell function during aging. Mice with endothelial specific SIRT1 overexpression on an apolipoprotein E (ApoE)−/− genetic background exhibit attenuated development of atherosclerotic lesions [70]. In contrast, SIRT1 insufficiency results in greater foam cell formation and atherosclerosis [71]. In the human endothelium, overexpression of SIRT1 prevents oxidative stress-induced senescence, whereas its inhibition leads to a premature senescence-like phenotype. Interestingly, immunosuppressant drugs, like sirolimus and everolimus, induce endothelial cellular senescence via SIRT1 down-regulation [72]. SIRT1 inhibition also impairs eNOS functionality, whereas its activation improves endothelial NO availability [73]. Hence, the SIRT1/NO axis may represent a relevant target against vascular senescence [74,75]. Interestingly enough, hyperglycaemia, obesity and hypertension are able to reproduce age-related effects on SIRT1 expression, thus strengthening a common role of SIRT1 in CVD and early aging.

SIRT1/p53/p66Shc axis

SIRT1-mediated deacetylation modulates the function of proteins via transcriptional and post-translational changes. A previous study reported that vascular p66Shc gene transcription may be the result of decreased promoter deacetylation due to down-regulation of SIRT1 [76]. Expression of p66Shc gene transcript and protein was significantly increased by different kinds of class III histone deacetylase inhibitors in human endothelial cells. Consistently, SIRT1 overexpression inhibited high glucose-induced p66Shc up-regulation, whereas SIRT1 knockdown exerted opposite effects. Moreover, endothelium-specific SIRT1 transgenic mice had blunted p66Shc gene and protein expression and improved endothelial function, as well as reduced accumulation of oxidative stress markers, compared with WT littermates [76]. The study by Zhou et al. [76] demonstrated that SIRT1 binds to the p66Shc promoter (−508 to −250 bp) where it deacetylates histone 3, thus suppressing gene transcription of the mitochondrial adaptor. Decreased SIRT1-dependent deacetylation is the main epigenetic mark responsible for p66Shc overexpression in the vasculature (Figure 1). Therefore, one can certainly postulate that SIRT1 and p66Shc stand along the same molecular pathway involved in the modulation of vascular and myocardial integrity during aging (Figure 1). Moreover, SIRT1 and p66Shc have molecular circuits with the tumour suppressor p53, critically involved in age-dependent mitochondrial disruption and apoptosis (Figure 1) [74]. Indeed, SIRT1 inhibition increases p53 acetylation and transcriptional activity [77]. In this regard, p53 is a master regulator of p66Shc transcription [78]. Accordingly, down-regulation of p66Shc expression as well as inhibition of p53 function in mice restored impairment of acetylcholine-induced vascular relaxations and increased NO bioavailability [78]. Taken together, these observations strongly suggest that p53 is a critical intermediate between the upstream regulator SIRT1 and its downstream target p66Shc (Figure 1).

SIRT-1 dependent regulation of energy balance

Age-dependent down-regulation of SIRT1 also favours acetylation of nuclear factor κB (NF-κB) p65, leading to its nuclear translocation and transcription of inflammatory genes [71]. The maintenance of sirtuin homoeostasis (SIRT1 and 3) is fundamental to repress detrimental pathways of arterial aging such as forkhead box O (FOXO) [75]. Inactivation of sirtuins during aging favours FOXO acetylation and subsequent transcription of FOXO-dependent genes favouring cellular apoptosis, cell cycle arrest and accumulation of ROS as well as metabolic derangements [79]. FOXOs are key downstream effectors of the phosphoinositide 3-kinase (PI3K)/Akt pathway that blocks FOXO target gene expression. Following stimulation of PI3K/Akt signalling by growth factors, Akt phosphorylates FOXOs on three conserved residues, which leads to their cytoplasmic sequestration and inactivation [75]. By contrast, Akt is inactive in the aged vasculature thus promoting FOXO-dependent transcriptional programmes, culminating with endothelial senescent phenotypes (Figure 1). Genetic studies in experimental animal models have clearly shown that many lifespan-extending mutations affect metabolic regulators and control circuits [80,81]. In this regard, particular attention deserves the regulation of LKB/AMP-activated protein kinase (AMPK) pathway by SIRT1 [82]. In the cytoplasm, SIRT1 deacetylates LKB1 leading to activation of the final effector enzyme AMPK, a central energy regulator involved in glucose homoeostasis, maintenance of cellular ATP levels and endothelial integrity via regulation of eNOS activity [74,75]. Perturbation of SIRT1/LKB/AMPK pathway leads to energy imbalance, cellular stress and activation of the apoptotic machinery thus contributing to arterial aging (Figure 1) [75,83].

Nuclear factor κB

Increasing evidence suggests that activation of the redox-sensitive transcription factor NF-κB plays a key role in endothelial activation and vascular inflammatory changes in aging [31]. NF-κB is an important transcription factor expressed in all mammalian cell types [84]. It regulates expression of genes controlling cell adhesion, proliferation, inflammation and redox state. Activation of NF-κB mediates vascular and myocardial inflammation in metabolic and age-related diseases [84]. A previous study has clearly demonstrated that endothelial suppression of NF-κB prolongs lifespan in mice and ameliorates obesity-induced endothelial insulin resistance [85]. Impaired insulin signalling is indeed an important hallmark linking metabolic disease with premature CV aging [86]. The relevance of these findings is supported by the notion that NF-κB protein is up-regulated in vascular endothelial cells isolated from obese and aged adults as compared with normoweight and young controls [87]. Moreover, age-dependent NF-κB activation is associated with systemic inflammation and impaired endothelial function [88]. Taken together, these data validate SIRT1 as a key orchestrator of arterial aging via modulation of oxidative stress, energy balance and vascular inflammation (Figure 1).

ECTOPIC VASCULAR CALCIFICATION

Vascular calcification represents an inevitable hallmark feature of vascular aging which favours atherothrombosis [89]. Global measures of coronary artery calcification were shown to independently predict both CV events and mortality [90,91]. Current investigations are now focusing on the possibility that ectopic calcification is mediated by cellular elements acquiring osteogenic phenotypes. Previous work clearly demonstrated that circulating osteoblastic cells isolated from human peripheral blood are able to calcify in vitro and in vivo [92]. These cells, which express the bone protein osteocalcin (OC) and bone alkaline phosphatase (BAP), have been considered circulating osteoprogenitor cells and might participate to vascular calcification and atherosclerosis. Indeed, preliminary clinical studies found that coronary atherosclerosis and arterial stiffening are associated with activation of an osteogenic programme in bone-marrow-derived cells [93]. A study has demonstrated that OC+/BAP+ cells originate from the myeloid lineage and retain monocyte/machrophage markers [94]. These cells, described as ‘myeloid calcifying cells’ (MCCs), can be differentiated from pheripheral blood mononuclear cells and ectopic calcifications in vivo. Interestingly, MCCs are significantly increased in patients with Type 2 diabetes and atherosclerotic lesions [94], thus providing an important link between CV risk factors and accelerated arterial aging. Among putative pathways involved, activation of the transcription factor Runx2 seems to play a major role in osteogenic differentiation (Figure 1). In conditions of oxidative stress, Akt activates Runx2 which in turn binds to the promoter of receptor activator of NF-κB ligand (RANKL), thus favouring changes of VSMC phenotype as well as differentiation of machrophages into osteoclast-like cells [95]. The Runx2/RANKL pathway is particularly active in senescent VSMCs, suggesting the importance of this signalling in age-related calcification and stiffening [96]. In summary, circulating (MCCs) and resident (VSMCs and machropahges) cells may significantly contribute to accelerate ectopic vascular calcification in aging (Figure 1).

AGE-DEPENDENT DECLINE OF VASCULAR HEALING PROCESS: CELLULAR AND MOLECULAR TARGETS

Recovery after ischaemia or infarction in any organ requires blood vessel growth [97]. The incidence of stroke, claudication and myocardial infarction all increase in older patients, and they have worse outcomes when ischaemia and infarction occurs [6]. Understanding the mechanisms involved in vascular repair is an important challenge to reduce CVD in aged individuals.

Endothelial progenitor and angiogenic outgrowth cells

Endothelial progenitor cells (EPCs) and early angiogenic outgrowth cells (EOCs) significantly contribute to endothelial repair, a phenomenon which is less efficient in aging [98]. EPCs are thought to directly mediate endothelial regeneration, whereas EOCs represent a heterogeneous pool of cell precursors, mostly of myeloid origin, which favour endothelial healing via a paracrine mechanism [99]. Although we are still far from a clear understanding of these processes, available knowledge support the notion that aging impairs the function of ex vivo-expanded EPCs [100]. Age-related EPC dysfunction is mediated by the imbalance between factors promoting growth, migration/survival and those enhancing oxidative stress/senescence. Hypoxia inducible factor 1α (HIF-1α) induces the expression of stromal cell-derived factor 1 (SDF-1) that enhances the recruitment of EPCs in injured or ischaemic tissues in mice. HIF-1α/SDF-1 signalling is impaired in aging and contributes to altered vascular repair (Figure 2) [101]. Interestingly, CV risk factors mirror the aging process by impairing EPCs functionality and, hence, vascular repair [102,103]. Indeed, the aging gene p66Shc is up-regulated in EPCs isolated from diabetic subjects and contributes to impaired migration and tube formation [104]. By contrast, vascular repair capacities are preserved in EPCs isolated from p66Shc−/− diabetic mice [104]. Hence, targeting p66Shc may contribute to rejuvenate EPCs thus improving cell functionality and angiogenic properties (Figure 2).

Mechanisms underlying age-dependent impairment of vascular healing

Figure 2
Mechanisms underlying age-dependent impairment of vascular healing

spred1, Sprouty-related, EVH1 domain-containing protein 1.

Figure 2
Mechanisms underlying age-dependent impairment of vascular healing

spred1, Sprouty-related, EVH1 domain-containing protein 1.

microRNAs

Recent work suggests that microRNAs (miRs) may be involved in the pathogenesis of age-related EPCs dysfunction (Figure 2) [105]. These small non-coding RNAs orchestrate EPCs functionality by regulating gene expression at the post-transcriptional level. In order to map the microRNA/gene expression signatures of EPCs senescence, Zhu et al. [106] performed a microRNA profiling and microarray analysis in lineage-negative bone marrow cells from young and aged as well as ApoE−/− mice. The analysis found miR-10A* and miR-21, and their common target gene high-mobility group AT-hook 2 (Hmga2) as critical regulators of EPCs senescence. Indeed, overexpression of miR-10A* and miR-21 in young EPCs suppressed Hmga2, leading to increased p16INK4a/p19ARF expression and impaired EPCs angiogenesis in vitro and in vivo. In contrast, suppression of miR-10A* and miR-21 in aged EPCs increased Hmga2 expression and rejuvenated EPCs, thus improving angiogenesis [106]. Furthermore, miR-34a was found to inhibit EPC-mediated angiogenesis by suppressing SIRT1 [107]. Recent studies showed that reprogramming angiomiR-126 in EOCs and circulating EPCs restores endothelial homeostasis and favours vascular healing [99,108]. These novel data suggest the possibility that in vitro reprogramming of human EPCs may improve vascular repair.

CONCLUSIONS

In the present paper, we have addressed key molecular mechanisms implicated in arterial aging and CVD. Premature activation of aging genes such as p66Shc and NF-κB as well as down-regulation of lifespan determinants JunD and SIRT1 may trigger senescence features leading to early CVD. Dysregulation of protective and detrimental genes caused by aging and other CV risk factors suggests the possibility to reprogramme such modifications in circulating and resident vascular wall cells. In this perspective, ex vivo reprogramming of autologous EPCs may rescue age-related cell dysfunction and restore angiogenic and reparative capacities after myocardial infarction or stroke. Future experimental and clinical research should address unmet scientific needs and provide insights for their clinical application in the context of CV aging (Figure 3).

Unmet scientific needs and future applications

Figure 3
Unmet scientific needs and future applications

BM, bone marrow; MRI, magnetic resonance imaging.

Figure 3
Unmet scientific needs and future applications

BM, bone marrow; MRI, magnetic resonance imaging.

FUNDING

Our own work was supported by the Swiss Heart Foundation and the Italian Ministry of Education, University and Research [grant number PRIN 2010–2011 (to F.C.).] F.P is the recipient of a PhD programme fellowship in Experimental Medicine at the University of Rome “Sapienza”.

Abbreviations

     
  • ALDH2

    aldehyde dehydrogenase 2

  •  
  • AMPK

    AMP-activated protein kinase

  •  
  • AP-1

    activated protein 1

  •  
  • ApoE

    apolipoprotein E

  •  
  • Arg II

    arginase II

  •  
  • BAP

    bone alkaline phosphatase

  •  
  • BH4

    tetrahydrobiopterin

  •  
  • CV

    cardiovascular

  •  
  • CVD

    cardiovascular disease

  •  
  • eNOS

    endothelial nitric oxide synthase

  •  
  • EOC

    early angiogenic outgrowth cell

  •  
  • EPC

    endothelial progenitor cell

  •  
  • fOXO

    Forkhead box O

  •  
  • HIF-1α

    hypoxia inducible factor 1α

  •  
  • MCC

    myeloid calcifying cell

  •  
  • NF-κB

    nuclear factor κB

  •  
  • OC

    osteocalcin

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • RANKL

    receptor activator of NF-κB ligand

  •  
  • ROS

    reactive oxygen species

  •  
  • SDF-1

    stromal cell-derived factor 1

  •  
  • VSMC

    vascular smooth muscle cell

  •  
  • WT

    wild-type

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