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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Nephrol Hypertens. Author manuscript; available in PMC Mar 1, 2011.
Published in final edited form as:
PMCID: PMC2943205
NIHMSID: NIHMS232611

Arterial Aging: a Journey into Subclinical Arterial Disease

Abstract

Purpose

Age-associated arterial alterations in cells, matrix, and biomolecules are the foundation for the initiation and progression of cardiovascular diseases in older persons. This review focuses on the latest advances on the intertwining of aging and disease within the arterial wall at the cell and molecular levels.

Recent findings

Endothelial dysfunction, VSMC proliferation/invasion/secretion, matrix fragmentation, collagenization and glycation are characteristics of an age-associated arterial phenotype that creates a microenvironment enriched with reactive oxygen species (ROS) for the pathogenesis of arterial disease. This niche creates an age-associated arterial secretory phenotype (AAASP), which is orchestrated by the concerted effects of numerous age-modified Ang II signaling molecules. Most of these biomolecular, cell, and matrix modifications that comprise the AASP can be elicited by experimental hypertension or atherosclerosis at a younger age. The arterial AAASP also shares features of a senescence associated secretory phenotype (SASP) identified in other mesenchymocytes, i.e. fibroblasts.

Summary

A subclinical AAASP evolves during aging. Targeting this subclinical AAASP may reduce the incidence and progression of the quintessential age-associated arterial diseases, i.e. hypertension and atherosclerosis.

Keywords: angiotensin II, arterial aging, arterial disease

Introduction

Morbidity and mortality due to the quintessential cardiovascular diseases, i.e., hypertension and atherosclerosis, leading to stroke, and heart failure increase exponentially with advancing age [1]. The number of Americans over 65 will more than double, from 34.8 million in 2000 (12 percent of the population) to 70.3 million in 2030 (20 percent of the total population) [1, 2]. Thus, the incidence and prevalence of arterial diseases will increase dramatically within this time-frame.

Age-associated arterial proinflammation is an early molecular manifestation of a chronic stress response i.e. overloading of ROS, of vascular endothelial and smooth muscle cells. That is orchestrating by an age-associated arterial secretory phenotype (AAASP) that involves the concerted effects of numerous Ang II biosignaling networks (Table 1) [3**, 4, 5*, 6, 7** 8]. Proinflammation fosters a biological “ battlefield” that nurtures arterial diseases (Table 1) [3**, 4, 5*, 6, 7** 8]. Arterial dilatation capacity declines after middle age, while arterial stiffness becomes markedly increased with aging [6]. Large arterial walls, in particular the intima, remodel with aging. Age-associated changes in cells and matrix magnify susceptibility to macro-and micro-environmental insults, rendering the arterial wall a fertile soil in which diseases, like hypertension or atherosclerosis flourish.

Table 1
Arterial Remodeling with Aging, Hypertension, and Atherosclerosis.

This review focuses on evidence to support the idea that arterial aging and arterial disease are interwoven at the cellular and molecular levels vis a vis an AAASP, and that realization of this intertwining of age-disease mechanisms may afford novel approaches to the prevention and treatment of atherosclerosis, hypertension, heart failure, and stroke.

Arterial wall aging

The arterial wall is remodeled by the joint effects of numerous protein alterations, in particular, Ang II signaling molecules, with advancing age.

Arterial remodeling

Age-associated arterial remodeling, particularly diffused intimal thickening, is evolutionarily conserved in various species, including rats, rabbits, nonhuman primates, and humans (Table 1). Thus, findings from experimental arterial aging studies in animals provide insights into the molecular and cellular mechanisms of arterial aging in humans. Age dramatically alters the volume and contents of the arterial intima in rats, nonhuman primates and humans [9, 10**, 11, 12, 13, 14, 15, 16]. Small disoriented vascular smooth muscle cells (VSMC), and collagen types I and type III markedly increase within the thickened intima of old rats [9, 13]. Old monkeys (~20 yrs) have a thickened intima containing cells and matrix beneath an intact endothelium, and nearly all of these cells stain positively for α-smooth muscle actin [11, 17].

Ang II Molecular signaling

Molecular elements of the angiotensin II (ang II) signaling cascade are upregulated both in aged arterial walls and play a causal role in arterial aging, and in the diseased vessel (Table 1). Ang II, angiotensin converting enzyme (ACE), Ang II receptor AT1 receptor are markedly increased with increasing age within the arterial wall, particularly, within the thickened intimae in several species, including humans [10**, 11, 12]. Interestingly, chymase, another angiotensin convertase, has also been detected in the arterial wall in aged nonhuman and human primates [11, 12].

Milk fat globule EGF-8 (MFG-E8)

Transcription and translation of arterial MFG-E8, a novel molecule is substantially increased with aging in several mammalian species, including humans [7**]. MFG-E8 expression is stimulated by Ang II and MFG-E8 colocalizes with Ang II and MCP-1 within aged aortic wall and [7**].

Monocyte chemostractant protein-1 (MCP-1)

Transcription, translation, activity of MCP-1, a powerful chemoattractant and a potential molecular event of intimal hypercellularity is increased within the aged arterial wall [15]. Interestingly, the MCP-1 gradient across the arterial wall from intima to media is substantially increased with aging [12, 15].

Calpain-1

Ang II induces calpain-1 expression in the aortic walls [10**]. The transcription, translation, and activity of calpain-1 are significantly up-regulated in aortae from old compared to young rats [10**].

Transforming growth factor-beta 1(TGF-β1)

TGF-β1 transcription, translation, and activity are increased within the aorta of old compared to young rats [14]. Latent associated protein (LAP)-bound TGF-β1 (~75 kDa) and the latent TGF binding protein-1 (LTBP-1)-bound to precursor TGF-β1 (190–250 kDa) also increase within the aged aortic wall, particularly within the thickened intimae [14].

Matrix metalloproteinase type II (MMP-2)

Levels of transcription, translation, and activity of MMP-2 are enhanced within the arterial wall, with aging [9, 10**, 11, 12, 13, 14, 16]. Enhanced arterial wall MMP-2 activity in situ is also observed of several species, including humans [9, 11, 12, 13, 14]. Furthermore, an increase of MMP-2 activity is attributable, not only to an enhanced transcription and translation, but also an imbalance activating and inhibiting factors, e.g., membrane-type1 matrix metalloproteinase (MT1-MMP) and tissue inhibitor of MMP-2 (TIMP2), respectively [11, 13].

ROS and NO bioavailability

Arterial NAD(P)H oxidase activation, a major source of ROS, increases with age [3**, 4, 18**, 19*, 20, 21, 22], while Cu/Zn SOD, Mg SOD, and extracellular matrix superoxide dismutase decrease in the arterial wall with increasing age [18**]. This imbalance of oxidase and dismutase consequently results in the increased in situ superoxide and hydrogen peroxides in the arterial wall with aging [18**, 19*].

ROS are major modulators of NO availability in the aging process [19*, 22]. The decrease in endothelial NO bioavailability with aging occurs concurrent with an increase in O2− production, both in the aorta and in the carotid artery [22]. The interaction of NO and O2− radicals will result in subsequent formation of peroxynitrite (ONOO-) [22]. Interventional studies indicate that increase breakdown of NO due to an augmented production of O2− is an important key mechanism leading to the decline of endothelium-dependent vasorelaxation with increasing age [22].

Arterial aging proteomics

A combined 2-D gel and isobaric tag for relative and absolute quantitation (iTRAQ) proteome approaches has identified 981 arterial proteins from young and old rats, of which, 50 (~5%) were shown to have a significantly different abundance with aging (Table 2) [7**]. Of these, 27 proteins are linked to the Ang II signaling pathway [7**].

Table 2
Differentially Abundant Proteins Identified by 2-D DIGE and iTRAQ with Aging

Specific age-associated effects on vascular cells and matrix

A concurrent remodeling of cells and matrix is the cornerstone of the aging vascular wall.

Endothelial cells (EC)

Aging impairs the structure, functions, and regeneration of the endothelium (Figure 1), which is tightly controlled by the NF-κb system [18**]. NF-κB is a key transcription factor that mediates Ang II signaling [18**]. Recent human studies show that NF-k-B p65 is increased in EC from older subjects [20]. Interestingly, the NF-kB inhibitor, salsalate, efficiently increases expression of the NF-κB inhibitor, IκB and reduces NF-κB in endothelial cells, reduces expression of the p47phox, nitrotyrosine from old subjects, and improves brachial artery flow-mediated dilatation in old subjects [21].

Figure 1
Illustration of potential molecular and cellular mechanisms for arterial proinflammation in the aging-to-disease journey.

Endothelial precursor cells (EPC)

Aging reduces EPC availability and impairs function, including homing, adhesion, spreading, proliferation and migration [23**]. Interestingly, the AT1 antagonist, valsartan, reduces Ang II accelerated senescence of EPC by upregulation of telomerase activity [24]; and polyphenol resverotrol inhibits EPC senescence to preserve the integrity of the arterial wall [25]. Furthermore, young rat serum is able to rescue the age-associated decline in the regenerative capability of EPC in vitro and in vivo [26**]. These findings suggest that a young niche could rescue aged EPC.

VSMC

The heterogeneity of VSMC phenotype substantially increases with aging.

Proliferation

Cultured VSMC from old rat aortae display accelerated growth rates compared to VSMC from young rats [27]. Additionally, compared to early passage VSMC from young rat aortae, old VSMC from old rat aortae have a greater percentage of their population in the S phase, and a lower percentage in the G0/G1 phase [28]. These differences are mediated by dysregulation of the cell cycle, impart, via ERK1/2 signaling that occurs during aging [29].

Invasiveness

Early passage aortic VSMC of old rats exhibit an exaggerated chemotactic PDGF-BB response, whereas cells from young aortae require several additional passages in culture to generate an equivalent response [30]. In response to a chemoattractant gradient of PDGE-BB and MCP-1 VSMC isolated from old aortae also exhibit increased invasion relative to young VSMC [12, 16]. This age difference is abolished or substantially reduced by Losartan, an AT1 atagonist, vCCI, an inhibitor of MCP-1/CCR2 signaling, GM 6001, an MMP inhibitor, and Ci 1, a calpain inhibitor, or by silencing MFG-E8 [7**, 8, 9, 10 **, 12, 15]. Thus, the increased age-associated VSMC invasion/migration is modulated by concurrent increases in elements of Ang II biosignaling networks.

Senescent proteins

Senescence-associated β-gal activity in the old rat arterial wall is detected in VSMC enriched with p16 and NOX4 [31, 32*]. Some aspects of VSMC senescence may be due to telomere shortening (replicative senescence) or to DNA damage response (DDR) to age-associated stress (chronic accumulation of ROS), known as stress-induced premature senescence (SIPS)(Figure 1) [33, 34*, 35**, 36**, 37]. Telomere shortening and DDR results in the phosphorylation of histones such as H2AX, the association of DNA repair enzymes and cofactors and activation of the transducer protein CHK2 [36**, 37]. These subsequently result in activation of effector molecules such as the breast cancer susceptibility gene BRCA1, E2F transcription factors, p53, p21, and p16 and in inactivation of effector molecules such as Rb and CDK4, and force VSMCs into G1 growth arrest [36**, 37].

Comparative analysis of the transcriptome profiles of early and late passage human arterial VSMC found a total of 327 differentially expressed probesets [38*]. These include IL-1β, IL-8, ICAM-1, and MCP-1 [38*]. Furthermore, senescent VSMC also secrete IL-1, IL-6/8, MCP-1, PAI-1, MMP-2 [33, 36**, 37], similar to a phenomenon found in senescent fiobroblasts, referred to as the senescence associated secretory phenotype (SASP) by Campisi J et al [34**, 35**]. Thus, senescent VSMC become “non-conventional” inflammation response (AAASP) cells. Like the SASP, the AAASP also likely allows damaged cells to communicate with the surrounding tissue as providing a complementary signaling role in arterial aging.

Extracellular matrix

Repeated interactions of EC and VSMC with extracellular matrix (ECM) via AASP including Ang II signaling molecules occurs within the arterial wall initiating a journey into subclinical arterial pathology. With aging, ECM becomes fragmented, collagenized calcified, and glycated (Figure 1) ([3**, 4]. Emerging evidence show that arterial advanced glycation end products (AGEs) accumulate in arteries with age in rodents, nonhuman primates, and humans [39, 40, 41]. Treatment with alagebrium (formerly named ALT7-111), a thiazolium derivative, can break established AGE crosslinks, reversing age-related increases in arterial stiffness in rats, nonhuman and human primates [39, 40, 41].

Links between arterial aging and hypertension

The aging process and essential hypertension cause similar functional and /or structural, and molecular modifications (Table 1). For example, sustained hypertension leads to functional and structural changes of the arterial wall in young subjects, similar to normotensive old ones [3**, 42, 43].. These alterations include the endothelial-dependent vascular dilatation, pulse wave velocity (PWV), and intimal medial thickness (IMT) [3**, 42, 43]. Further, hypertension accelerates and intensifies age-associated remodeling of the arterial wall and modifications of its mechanical properties and complications including atherosclerosis, stroke, and heart failure [44, 45, 46].

Findings from experimental studies with animals provide insights into the molecular and cellular mechanisms of the interaction of aging and hypertension in humans. In vivo chronic infusion of FXBN rats with Ang II at a subpressor doses increases MMP2 expression and activity, and increases collagen production within the arterial wall [9]; at higher concentrations sufficient to elicit an increase in arterial pressure of a magnitude similar to that of old, and an increases of MMP2, calpain-1, and TGF-β1 activity [9]. Ang II infusion also imparts structural and molecular characteristics of arteries of old, untreated rats to the central arteries of young rats [9, 10**]. Chronic infusion of phenylephrine (PE), an adrenergic transmitter (α1-AR) known to increase with age [9, 47], into young rats, increases arterial wall Ang II levels, and reproduces Ang II effects [9]. Thus, Ang II signaling can indeed mediate structural, biochemical, and functional features of aging within the arterial wall of young rats and produce hypertension. These results complement those of other studies that have demonstrated that chronic ACE inhibition or AT1 receptor blockade at an early age markedly delays the progression of age-associated arterial remodeling in rodents [48, 49]. In addition, the production of downstream Ang II signaling molecules, TGF-β1 and ROS, and blood pressure increase concomitantly in SHR compared to WKY rats with aging [50, 51, 52]. These findings suggest that Ang II signaling plays a magnified role in the pathogenesis of hypertension disorders with aging, which may reduce lifespan. Indeed, disruption of the Agtr 1a gene that encodes AT1, markedly increases life span in mice via an enhanced number of mitochondria and upregulation of the prosurvival genes nicotinamide phosphoribosyltransferase and sirtuin 3 [53**]. Further, lifelong treatment with the AT1 blocker, fonsartan, in young stroke-prone spontaneously hypertensive rats (SHR-sp) doubles the lifespan to 30 months by alleviating complications of hypertension, compared to the normotensive Wistar-Kyoto (WKY) rats [54].

Atherosclerosis with aging

The aging process and inflammatory components of pre-lipid deposition aspects of atherosclerosis cause similar functional and /or structural, and molecular modifications (Table 1). At autopsy, an advanced grade of arterial atherosclerosis is observed in older compared to younger patients [55]. Animal studies show that although similar age alteration in plasma lipid profile, more prevalent and extensive fatty lesions occur in old mice, rabbit, nonhuman primates compared to young [56, 57, 58]. Recently, findings from proteomic studies reveal insights into similar mechanisms involved in arterial aging and atherosclerosis [7**, 59]. In a proteomic analysis of 35 human coronary atherosclerotic plaques that identified a total of 806 proteins [59], many of the abundant proteins in the atherosclerotic intimae are those that increase in the aged arterial wall (Table 2), including TGF-β1, periostin, MFG-E8, and PDGF-β [59], providing additional support for the idea that the aged arterial wall with enhanced ang II signaling is fertile soil that nurtures atherosclerosis. Further, AT1a deficiency, which effectively protects ApoE−/− mice from the initiation and progression of atherogenesis, exhibits the inhibition of age-associated increases in expression or activation of collagen, 22phox, and MMP-2/9 [60]. Endothelium restricted inhibition of NF-κB activation, achieved by ablation of NEMO/IKKg, or by expression of dominant- negative IκBa specifically in endothelial cells, potently reduces atherosclerotic plaque formation in ApoE−/− mice fed with a cholesterol rich diet with aging. [61**]. The accelerated vascular injury in older LDLR−/− mice is closely associated with the profound inability to mount an antioxidant response [62*].

Conclusion

The novel AAASP concept provides an explanation for observation that the arterial wall of younger animals in response to experimental induction of low-grade chronic inflammation, e.g., by hypertension or early atherosclerosis, is transformed into a phenotype that is strikingly similar to that which develops during aging [3**, 4, 63]. Thus, “aging”-associated arterial changes and those associated with hypertension and atherosclerosis are fundamentally intertwined at the cellular and molecular levels (Table 1) [3**]. In humans, other well-known “life-style” risk factors (e.g., altered lipid metabolism due to dietary indiscretion, smoking, and lack of exercise) likely interact with this arterial substrate that has been altered during aging, rendering the aging artery a fertile soil that facilitates the initiation and magnified progression of arterial diseases [3**, 4]. Lifestyle and pharmacologic interventions have already proved to be effective in preventing or ameliorating vascular disease associated with aging [3**, 4]. The subclinical AAASP affords novel targets to reduce the incidence and progression of the quintessential age-associated arterial diseases, i.e. hypertension and atherosclerosis.

Acknowledgments

Funding

This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

Footnotes

Conflicts of interest

None

References and recommended reading

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