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J Appl Physiol 106: 333-337, 2009. First published November 20, 2008; doi:10.1152/japplphysiol.91360.2008
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REVIEW

HIGHLIGHTED TOPIC
Physiology of the Aging Vasculature

The telomerase tale in vascular aging: regulation by estrogens and nitric oxide signaling

Antonella Farsetti,1 Annalisa Grasselli,1 Silvia Bacchetti,1 Carlo Gaetano,2 and Maurizio C. Capogrossi2

1Department of Experimental Oncology, Molecular Oncogenesis Laboratory, Experimental Research Center, Regina Elena Institute and Institute of Neurobiology and Molecular Medicine, National Research Council, Rome, Italy; and 2Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy

ABSTRACT

Hormones and nitric oxide (NO), a free radical, are ancestral molecules, conserved through evolution, that modulate many aspects of the physiology and pathophysiology of living organisms by regulating transcription of genes involved in development, metabolism, and differentiation. Of interest, both estrogen and NO signaling, specifically through the estrogen receptor-{alpha} (ER{alpha}) and the endothelial isoform of the nitric oxide synthase (eNOS), have been shown to counteract endothelial senescence through a shared downstream effector, the catalytic subunit of human telomerase (hTERT), a key molecule in the aging process. Since aging is the first and most relevant risk factor in cardiovascular diseases, it is tempting to speculate that hTERT may be at the cross point between the NO and estrogen pathways. The present review will focus on the evolutionary and molecular aspects linking eNOS, ERs, and hTERT in counteracting the process of endothelial cell aging.

estrogen receptor; endothelial nitric oxide synthase

HORMONE MOLECULES, which are involved in the regulation of the endocrine system, modulate many aspects of the physiology and pathophysiology of living organisms. Hormone action is mediated by members of the nuclear hormone receptor super family whose progenitor is an orphan receptor, an ancestral receptor for which a ligand was identified subsequently (27). The nuclear hormone receptors are in fact evolved forms of receptor capable of regulating transcription of a variety of target genes involved in development, metabolism, and differentiation upon interaction with a hormone molecule (53, 54). Formation of the hormone-receptor complex is the primum movens in hormone-dependent transcription, defining the hormone receptors as ligand-dependent transcription factors. Ligands that usually exhibit high affinity for specific receptors may have agonist or antagonist function. Thus they can either induce or repress transcription of target genes (53, 54), contributing to the living organism's adaptation to environmental changes.

Nitric oxide (NO) is a free radical recognized as an ancestral regulator of various biological functions. Specifically, in mammals NO has been proposed to play a master role in major pathophysiological processes, including regulation of endothelial function, blood pressure, and muscle and heart organogenesis during development (6, 20, 44). NO is produced by a family of three isoforms of NO synthases (NOS) that catalyze the synthesis of NO from L-arginine: neuronal (nNOS/NOS1), inducible (iNOS/NOS2), and endothelial (eNOS/NOS3), reflecting the tissues of origin of the original protein and cDNA isolates. Although the nNOS and eNOS isoforms were initially detected in neurons and endothelial cells, respectively, their expression is more widely distributed, being virtually present in all cell types. Following a rise in intracellular calcium, eNOS and nNOS are activated by calmodulin binding and produce nanomolar concentrations of NO for seconds or minutes. In contrast to this, iNOS, which exhibits the highest affinity for calmodulin, is permanently active throughout its life (hours/days) and synthesizes micromolar concentrations of NO in the absence of changes in calcium levels (31). Both NO and estrogens have been shown to counteract senescence in the endothelium (17, 19, 48, 55). Of interest, their effects are channeled through a common downstream effector, hTERT, the catalytic subunit of human telomerase. hTERT itself is a key molecule in the aging process, and several therapeutic approaches targeting this enzyme have been pursued with the goal of delaying senescence in a variety of experimental systems, including endothelial cells (2, 14, 22, 29, 30, 41).

In the effort to address the intriguing issue raised by Lakatta in his editorial in the Journal of Applied Physiology (23a), on the need to understand the mechanisms determining the loss of plasticity of the arterial wall that accompanies aging and progressively compromises vasculature structure and function, we will focus on dissecting, at the molecular level, the contribution of eNOS and estrogen receptor (ER) on the regulation of a key aging target such as telomerase in the endothelial microenvironment.

TELOMERASE ACTIVITY AND VASCULAR SENESCENCE

Numerous studies over the last decade have described an association between telomere shortening with cell division in the absence of telomerase activity and endothelial aging in several experimental systems in vivo and in vitro (22). In humans, endothelial dysfunction is well documented in aged arteries, and senescence-associated phenotypes have been described in the atherosclerotic lesions of human coronary arteries (28, 29). In keeping with these observations, we obtained evidence (38) of higher telomerase activity in polymorphonuclear neutrophils (PMN) in the coronary plaques of patients with unstable angina (UA) compared with their peripheral blood. This finding of telomerase enhancement in resident PMN in unstable coronary plaques is in agreement with delayed PMN apoptosis in UA patients (11). This suggests local extended lifespan and prolonged activity of these inflammatory cells in the early phases of instability. Although further research is required for a better understanding of the precise relationship between telomerase and neutrophil function in unstable coronary plaques, the study underscores the biological relevance of telomerase activation in the microenvironment of the atherosclerotic plaque. Similar results have been obtained in telomerase-deficient mouse models (24), in which, after successive generations leading to substantial telomere erosion, the animals have a shortened lifespan and exhibit age-associated changes such as reduced capacity to respond to stress (46) or impaired neovascularization (9), at least in part attributable to telomere dysfunction.

In an independent line of research in a rat model of hindlimb ischemia, we (58) demonstrated that telomerase is also an important downstream effector of VEGF-mediated neovascularization. Since age-dependent telomere dysfunction contributes to reduced cell viability, altered differentiation, and impaired regenerative/proliferative responses (3, 9, 24, 46), the study was conducted on both young and old animals (58). Regardless of age, acute hindlimb ischemia reduced not only capillary density, as expected, but also TERT expression and telomerase activity evaluated in vascular structures and muscle fibers (Fig. 1, A and B; and data not shown). Treatment with VEGF165 reversed these effects in both young and old animals, although the extent and timing of these responses were inversely correlated with age (Fig. 1, A and B). The rapid onset of the angiogenic process after expression of telomerase, detectable within a few days in vivo and within 12–24 h in vitro, would seem to exclude a telomerase effect mediated by a substantial lengthening of telomeres. Rather, we favor a model in which telomerase acts as survival factor, protecting chromosome ends and thereby protecting cells from apoptosis (5, 58).


Figure 1
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  		Fig. 1. VEGF induces angiogenesis and upregulates telomerase activity in vivo. Normoperfused or ischemic rat adductor muscles were collected from young (4 mo) and old (22–28 mo) male Wistar rats at 3, 8, and 14 days after intramuscular injection of saline (saline), a control adenoviral vector (AdNull), or an adenoviral vector carrying the human isoform of VEGF165 (AdVEGF165) or the bacterial beta-galactosidase gene (AdLacZ) as indicated. A: capillary density was evaluated on hematoxylin- and eosin-stained sections. Values were expressed as counts/mm2. B: telomerase activity was measured by TRAP assays. The results shown are from 3 of randomly chosen rats out of 12 after 3 days (young) and 8 days (old) of treatment, i.e., at the time the peak effect was achieved. HeLa and HeLa heat-inactivated (HI) extracts were used as positive and negative controls, respectively. IC, internal control. VEGF165 enhanced capillary density in both groups. In young rats values were significantly higher than in controls at each time point, whereas in old animals a statistically significant angiogenic response was achieved only at 14 days. Telomerase activity was low but detectable in the skeletal muscles of normoperfused animals of both groups, was virtually absent following ischemia, but was substantially rescued by 3 days in young and by 8 days in old rats. Expression of the telomerase reverse transcriptase (TERT) protein (data not shown), detectable in muscle fibers and vascular structures of young and old normoperfused animals, was also downregulated by ischemia and rescued by VEGF165 treatment in both groups, although to a lower extent in aged rats. *Statistical significance. [Adapted from Zaccagnini et al. (58).]

 
Mechanistically, neoangiogenesis in the above system involved 1) VEGF-dependent activation of telomerase through the NO pathway (34), and 2) telomerase-dependent protection from apoptosis (13, 23). Regardless of the mechanism, the role of TERT as an angiogenic factor and downstream effector of VEGF, particularly in the case of old animals, encourages development of novel gene therapy interventions in ischemia.

eNOS/NO AND LIGAND-ACTIVATED ER SIGNALING IN THE REGULATION OF TELOMERASE

Telomerase has been associated with the proliferative capacity, survival, and function of endothelial cells (33, 55–57), cardiomyocytes (25, 42, 43), and cardiac stem cells (52). Overall, these observations are consistent with a similar role of the enzyme during angiogenesis both in vivo and in vitro (56, 58). Furthermore, pharmacological inhibition of NO production abrogated VEGF165-dependent induction of telomerase in vitro, whereas expression of a constitutively active phosphomimetic eNOS mutant induced TERT promoter activity at levels similar to those induced by VEGF (58). These results indicate that NO synthesis plays an important role in the VEGF-mediated angiogenic effect (35) and provide a link between the angiogenic factor and telomerase expression and function.

Estrogens are atheroprotective molecules with a beneficial effect on the cardiovascular system (16, 39). This effect is mediated in part by NO production due to estrogen-dependent activation of eNOS via genomic and nongenomic mechanisms (15, 18, 26, 32, 47, 49, 51). Estrogens acting through ERs confer critical protection to the cardiovascular system, modulating several important physiological adaptive responses in the human endothelium: antiatherogenic actions, vasodilation, and preservation of vascular integrity. In previous work, we provided evidence for a direct role of 17β-estradiol (E2)-activated ERs in the transcriptional regulation of hTERT, and particularly in the activation of the enzyme through estrogen-dependent chromatin remodeling of the hTERT genomic sequences at specific estrogen response elements (ERE) (30, 36, 37). Interestingly, several reports have demonstrated that hTERT is also induced by medications, such as aspirin, statins, and thiazolidinediones (2, 8, 14, 41) known to exert a beneficial effect on cardiovascular diseases.

In the vascular wall eNOS is the principal source of NO (21, 44), and, intriguingly, NO signaling is also involved in hTERT regulation as originally reported by Vasa et al. (55). In agreement with these observations Hayashi et al. (17) demonstrated in endothelial cells that NO prevents senescence in cooperation with the antisenile effect mediated by the estrogen treatment, suggesting a direct involvement of the eNOS/NO and E2/ER signaling pathways in delaying endothelial senescence.

These and other reports strongly suggest the existence of a functional link between the ERs and eNOS signaling pathways, a link also supported by the fact that NO and estrogen are both important mediators of signal transduction in a variety of tissues (4). Our original hypothesis was that eNOS may function as a coactivator of ERs in gene transcription and that putative formation of an active eNOS/ER complex would cause local production of NO with major regulatory effects on endothelial cell function and vascular system. Indeed, in a recent study we found evidence of a direct cooperation between the ERs and eNOS pathways through hTERT transcriptional coregulation (12). This study demonstrated the existence of a molecular circuitry of intracellular control of telomerase regulation, mediated essentially by the association between ER{alpha} and eNOS. The novelty of our model resides in the identification of 1) an innovative role for eNOS as an essential cofactor of the ER{alpha}, at least in the context of the human endothelium; and 2) a combinatorial complex eNOS/ER{alpha} with a remodeling effect on chromatin, leading to transcriptional regulation of target genes, such as hTERT, extremely sensitive to estrogen stimulation as well as to variations in the intracellular levels of oxygen and NO. Furthermore, different intracellular levels of NO, brought about by modulation of eNOS activity by the phosphoinositide 3-kinase (PI3K)-Akt pathway and posttranslational modifications (phosphorylation or acetylation) (1, 45) regulate several intracellular targets via cysteine S-nitrosylation, directly affecting the structure and function of proteins (6) including enzymes with epigenetic roles such as the histone deacetylase 2 (40).

Overall, these findings fit with the current model that assigns to telomerase an important role in cardiovascular disorders and in events strictly related to the angiogenesis process, even in oncological diseases (7, 10, 50). Figure 2 illustrates a schematic model of the eNOS/ER{alpha} combinatorial complex onto the hTERT ERE genomic sites as assessed by Re-chromatin immunoprecipitation (Re-ChIP) assays. Colocalization of the two factors was also detected by confocal microscopy analysis in the cytoplasm (12). In primary pulmonary endothelial cells derived from eNOS–/– mice, loss of telomerase activity was rescued by exogenous eNOS or an NO donor while responsiveness to E2 demanded the presence of an active enzyme. This observation clearly indicates that NO is a master signaling molecule in the regulation of telomerase in the endothelium and reveals a hierarchical relationship between eNOS/NO activation and hTERT expression and activity. However, whether replicative senescence is caused directly by reduced eNOS/NO or reduced telomerase activity remains to be more clearly defined. Moreover, the results obtained on silencing of the eNOS and/or ER genes by genetic or pharmacological approaches in an endothelial microenvironment described in Grasselli et al. (12) may foster innovative therapeutic approaches based on the use of agonists or antagonists of estrogen action in combination with selective modulators of eNOS with the aim of delaying the onset of age-dependent endothelial dysfunction (12, 59).


Figure 2
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  		Fig. 2. Schematic illustration of the mechanism involved in estrogen receptor- and endothelial nitric oxide synthase (eNOS)-induced hTERT transcription. Ligand (E2) activated-estrogen receptor-{alpha} (ER{alpha}) and eNOS phosphorylated in serine 1177 (P) are both present in the caveolae. Colocalization of the 2 factors is detected by confocal microscopy [Grasselli et al. (12)] in the cytoplasm (probably in the endoplasmic reticulum), and their functional complex is present in the nucleus where it activates hTERT transcription. Dark gray circles represent histones. ERE, estrogen response element; hTERT, catalytic subunit of human telomerase.

 
Although the most important questions about the impact of aging on the quality of human life are still awaiting answers, undoubtedly this has been a central issue for very long, at least since the time of ancient Rome, as demonstrated by Cicero's essay "De Senectute" (see Fig. 3), debating aspects and consequences of elderly life.


Figure 3
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  		Fig. 3. Cover of Marcus Tullius Cicero's essay "De Senectute," written in 44 BC, one year before his death, from De Officiis (Christopher Froschouer, 1560).

 
GRANTS

This research was supported by the Ministero del Lavoro, della Salute e delle Politiche Sociali (to A. Farsetti and M. C. Capogrossi); Association Francaise contre les Myopathies (AFM) Grant no. MNM2-06 and Muscular Dystrophy Association (MDA) grant no. 88202 to C. Gaetano; and Fondo per gli investimenti della Ricerca di Base (FIRB) grant no. RBLA035A4X-1-FIRB, UE FP6 grant no. UE-LHSB-CT-04-502988, and no. DdT2-06 to M. C. Capogrossi.

FOOTNOTES


Address for reprint requests and other correspondence: A. Farsetti, Dept. of Experimental Oncology, Molecular Oncogenesis Laboratory, Experimental Research Center, Regina Elena Institute and Institute of Neurobiology and Molecular Medicine, National Research Council, Rome, Italy (e-mail: afarsetti{at}gmail.com)

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