Endothelial Cell Senescence and Age-Related Vascular Diseases

Xiao-Li Tian^,,
Yang Li

Department of Human Population Genetics and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine (IMM), Peking University, Beijing 100871, China

More Information

Corresponding author: E-mail address: xiaolitian2013@163.com (Xiao-Li Tian)

摘要

- /
- /
- /
- /
Abstract: Advanced age is an independent risk factor for ageing-related complex diseases, such as coronary artery disease, stroke, and hypertension, which are common but life threatening and related to the ageing-associated vascular dysfunction. On the other hand, patients with progeria syndromes suffer from serious atherosclerosis, suggesting that the impaired vascular functions may be critical to organismal ageing, or vice versa. However, it remains largely unknown how vascular cells, particularly endothelial cell, become senescent and how the senescence impairs the vascular functions and contributes to the age-related vascular diseases over time. Here, we review the recent progress on the characteristics of vascular ageing and endothelial cell senescence in vitro and in vivo, evaluate how genetic and environmental factors as well as autophagy and stem cell influence endothelial cell senescence and how the senescence contributes to the age-related vascular phenotypes, such as atherosclerosis and increased vascular stiffness, and explore the possibility whether we can delay the age-related vascular diseases through the control of vascular ageing.
- Endothelial cell senescence /
- Genetic /
- Vascular ageing /
- Age-related diseases /
- Stem cell

HTML全文

参考文献(161)

[1]	Armour, S.M., Baur, J.A., Hsieh, S.N. et al. Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy Aging (Albany NY), 1 (2009),pp. 515-528
[2]	Asai, J., Takenaka, H., Kusano, K.F. et al. Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling Circulation, 113 (2006),pp. 2413-2424
[3]	Bae, H.T., Sebastiani, P., Sun, J.X. et al. Genome-wide association study of personality traits in the long life family study Front. Genet., 4 (2013),p. 65
[4]	Barton, M., Cosentino, F., Brandes, R.P. et al. Anatomic heterogeneity of vascular aging: role of nitric oxide and endothelin Hypertension, 30 (1997),pp. 817-824
[5]	Beekman, M., Blanche, H., Perola, M. et al. Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study Aging Cell, 12 (2013),pp. 184-193
[6]	Behnke, B.J., Prisby, R.D., Lesniewski, L.A. et al. Influence of ageing and physical activity on vascular morphology in rat skeletal muscle J. Physiol., 575 (2006),pp. 617-626
[7]	Bell, J.T., Tsai, P.C., Yang, T.P. et al. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population PLoS Genet., 8 (2012),p. e1002629
[8]	Bernardini, D., Ballabio, E., Mariotti, M. et al. Differential expression of EDF-1 and endothelial nitric oxide synthase by proliferating, quiescent and senescent microvascular endothelial cells Biochim. Biophys. Acta, 1745 (2005),pp. 265-272
[9]	Bierman, E.L. In Vitro, 14 (1978),pp. 951-955
[10]	Bode-Boger, S.M., Martens-Lobenhoffer, J., Tager, M. et al. Aspirin reduces endothelial cell senescence Biochem. Biophys. Res. Commun., 334 (2005),pp. 1226-1232
[11]	Bojovic, B., Crowe, D.L. Chronologic aging decreases tumor angiogenesis and metastasis in a mouse model of head and neck cancer Int. J. Oncol., 36 (2010),pp. 715-723
[12]	Bonithon-Kopp, C., Touboul, P.J., Berr, C. et al. Relation of intima-media thickness to atherosclerotic plaques in carotid arteries. The Vascular Aging (EVA) Study Arterioscler. Thromb. Vasc. Biol., 16 (1996),pp. 310-316
[13]	Boyden, S.E., Kunkel, L.M. High-density genomewide linkage analysis of exceptional human longevity identifies multiple novel loci PLoS ONE, 5 (2010),p. e12432
[14]	Brandes, R.P., Fleming, I., Busse, R. Endothelial aging Cardiovasc. Res., 66 (2005),pp. 286-294
[15]	Brodsky, S.V., Gealekman, O., Chen, J. et al. Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by Ebselen Circ. Res., 94 (2004),pp. 377-384
[16]	Brown, W.R., Thore, C.R. Review: cerebral microvascular pathology in ageing and neurodegeneration Neuropathol. Appl. Neurobiol., 37 (2011),pp. 56-74
[17]	Cardus, A., Uryga, A.K., Walters, G. et al. SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence Cardiovasc. Res., 97 (2013),pp. 571-579
[18]	Carracedo, J., Buendia, P., Merino, A. et al. Cellular senescence determines endothelial cell damage induced by uremia Exp. Gerontol., 48 (2013),pp. 766-773
[19]	Chang, E., Harley, C.B. Telomere length and replicative aging in human vascular tissues Proc. Natl. Acad. Sci. USA, 92 (1995),pp. 11190-11194
[20]	Chang, E.I., Loh, S.A., Ceradini, D.J. et al. Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia Circulation, 116 (2007),pp. 2818-2829
[21]	Chang, H., Rha, S.Y., Jeung, H.C. et al. Telomerase- and angiogenesis-related gene responses to irradiation in human umbilical vein endothelial cells Int. J. Mol. Med., 31 (2013),pp. 1202-1208
[22]	Chen, J., Goligorsky, M.S. Premature senescence of endothelial cells: Methusaleh's dilemma Am. J. Physiol. Heart Circ. Physiol., 290 (2006),pp. H1729-H1739
[23]	Chen, J., Huang, X., Halicka, D. et al. Contribution of p16INK4a and p21CIP1 pathways to induction of premature senescence of human endothelial cells: permissive role of p53 Am. J. Physiol. Heart Circ. Physiol., 290 (2006),pp. H1575-H1586
[24]	Cho, K.A., Ryu, S.J., Oh, Y.S. et al. Morphological adjustment of senescent cells by modulating caveolin-1 status J. Biol. Chem., 279 (2004),pp. 42270-42278
[25]	Choi, S.Y., Oh, B.H., Bae Park, J. et al. Age-associated increase in arterial stiffness measured according to the cardio-ankle vascular index without blood pressure changes in healthy adults J. Atheroscler. Thromb., 20 (2013),pp. 911-923
[26]	Cines, D.B., Pollak, E.S., Buck, C.A. et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders Blood, 91 (1998),pp. 3527-3561
[27]	Clopath, P., Muller, K., Staubli, W. et al. Haemostasis, 8 (1979),pp. 149-157
[28]	Coleman, P.R., Hahn, C.N., Grimshaw, M. et al. Blood, 116 (2010),pp. 4016-4024
[29]	Deelen, J., Beekman, M., Uh, H.W. et al. Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited Aging Cell, 10 (2011),pp. 686-698
[30]	Di, Q., Cheng, Z., Kim, W. et al. Impaired cross-activation of beta3 integrin and VEGFR-2 on endothelial progenitor cells with aging decreases angiogenesis in response to hypoxia Int. J. Cardiol., 168 (2013),pp. 2167-2176
[31]	Duckles, S.P. Influence of age on vascular adrenergic responsiveness Blood Vessels, 24 (1987),pp. 113-116
[32]	Ducray, C., Pommier, J.P., Martins, L. et al. Telomere dynamics, end-to-end fusions and telomerase activation during the human fibroblast immortalization process Oncogene, 18 (1999),pp. 4211-4223
[33]	ElSharawy, A., Keller, A., Flachsbart, F. et al. Genome-wide miRNA signatures of human longevity Aging Cell, 11 (2012),pp. 607-616
[34]	Erusalimsky, J.D., Skene, C. Mechanisms of endothelial senescence Exp. Physiol., 94 (2009),pp. 299-304
[35]	Fenton, M., Barker, S., Kurz, D.J. et al. Cellular senescence after single and repeated balloon catheter denudations of rabbit carotid arteries Arterioscler. Thromb. Vasc. Biol., 21 (2001),pp. 220-226
[36]	Fishman, J.A., Ryan, G.B., Karnovsky, M.J. Endothelial regeneration in the rat carotid artery and the significance of endothelial denudation in the pathogenesis of myointimal thickening Lab. Invest., 32 (1975),pp. 339-351
[37]	Foreman, K.E., Tang, J. Molecular mechanisms of replicative senescence in endothelial cells Exp. Gerontol., 38 (2003),pp. 1251-1257
[38]	Freedman, D.A., Folkman, J. CDK2 translational down-regulation during endothelial senescence Exp. Cell Res., 307 (2005),pp. 118-130
[39]	Gentilini, D., Mari, D., Castaldi, D. et al. Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians' offspring Age (Dordr), 35 (2013),pp. 1961-1973
[40]	George, J., Afek, A., Abashidze, A. et al. Transfer of endothelial progenitor and bone marrow cells influences atherosclerotic plaque size and composition in apolipoprotein E knockout mice Arterioscler. Thromb. Vasc. Biol., 25 (2005),pp. 2636-2641
[41]	Gombar, S., Jung, H.J., Dong, F. et al. Comprehensive microRNA profiling in B-cells of human centenarians by massively parallel sequencing BMC Genomics, 13 (2012),p. 353
[42]	Groleau, J., Dussault, S., Turgeon, J. et al. Accelerated vascular aging in CuZnSOD-deficient mice: impact on EPC function and reparative neovascularization PLoS ONE, 6 (2011),p. e23308
[43]	Gu, D., Reynolds, K., Wu, X. et al. Prevalence, awareness, treatment, and control of hypertension in China Hypertension, 40 (2002),pp. 920-927
[44]	Haendeler, J., Hoffmann, J., Diehl, J.F. et al. Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells Circ. Res., 94 (2004),pp. 768-775
[45]	Hagensen, M.K., Raarup, M.K., Mortensen, M.B. et al. Circulating endothelial progenitor cells do not contribute to regeneration of endothelium after murine arterial injury Cardiovasc. Res., 93 (2012),pp. 223-231
[46]	Hagensen, M.K., Shim, J., Thim, T. et al. Circulating endothelial progenitor cells do not contribute to plaque endothelium in murine atherosclerosis Circulation, 121 (2010),pp. 898-905
[47]	Hampel, B., Fortschegger, K., Ressler, S. et al. Exp. Gerontol., 41 (2006),pp. 474-481
[48]	Han, J., Pan, X.Y., Xu, Y. et al. Curcumin induces autophagy to protect vascular endothelial cell survival from oxidative stress damage Autophagy, 8 (2012),pp. 812-825
[49]	Hannum, G., Guinney, J., Zhao, L. et al. Genome-wide methylation profiles reveal quantitative views of human aging rates Mol. Cell, 49 (2013),pp. 359-367
[50]	Hansson, G.K., Chao, S., Schwartz, S.M. et al. Aortic endothelial cell death and replication in normal and lipopolysaccharide-treated rats Am. J. Pathol., 121 (1985),pp. 123-127
[51]	Hayashi, T., Yano, K., Matsui-Hirai, H. et al. Nitric oxide and endothelial cellular senescence Pharmacol. Ther., 120 (2008),pp. 333-339
[52]	Hayflick, L. Current theories of biological aging Fed. Proc., 34 (1975),pp. 9-13
[53]	Hayflick, L., Moorhead, P.S. The serial cultivation of human diploid cell strains Exp. Cell. Res., 25 (1961),pp. 585-621
[54]	Hernandez, D.G., Nalls, M.A., Gibbs, J.R. et al. Distinct DNA methylation changes highly correlated with chronological age in the human brain Hum. Mol. Genet., 20 (2011),pp. 1164-1172
[55]	Heyn, H., Li, N., Ferreira, H.J. et al. Distinct DNA methylomes of newborns and centenarians Proc. Natl. Acad. Sci. USA, 109 (2012),pp. 10522-10527
[56]	Higashi, Y., Pandey, A., Goodwin, B. et al. Insulin-like growth factor-1 regulates glutathione peroxidase expression and activity in vascular endothelial cells: implications for atheroprotective actions of insulin-like growth factor-1 Biochim. Biophys. Acta, 1832 (2013),pp. 391-399
[57]	Hooijberg, E., Ruizendaal, J.J., Snijders, P.J. et al. J. Immunol., 165 (2000),pp. 4239-4245
[58]	Huynh, J., Nishimura, N., Rana, K. et al. Age-related intimal stiffening enhances endothelial permeability and leukocyte transmigration Science Translat. Med., 3 (2011),p. 112ra122
[59]	Ii, M., Takenaka, H., Asai, J. et al. Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury Circ. Res., 98 (2006),pp. 697-704
[60]	Ito, T., Yagi, S., Yamakuchi, M. MicroRNA-34a regulation of endothelial senescence Biochem. Biophys. Res. Commun., 398 (2010),pp. 735-740
[61]	Itoh, Y., Toriumi, H., Yamada, S. et al. Resident endothelial cells surrounding damaged arterial endothelium reendothelialize the lesion Arterioscler. Thromb. Vasc. Biol., 30 (2010),pp. 1725-1732
[62]	Iwakura, A., Luedemann, C., Shastry, S. et al. Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury Circulation, 108 (2003),pp. 3115-3121
[63]	Jiang, P., Mizushima, N. Autophagy and human diseases Cell Res., 24 (2014),pp. 69-79
[64]	Kaess, B.M., Rong, J., Larson, M.G. et al. Aortic stiffness, blood pressure progression, and incident hypertension JAMA, 308 (2012),pp. 875-881
[65]	Kerber, R.A., O'Brien, E., Boucher, K.M. et al. A genome-wide study replicates linkage of 3p22-24 to extreme longevity in humans and identifies possible additional loci PLoS ONE, 7 (2012),p. e34746
[66]	Kim, K.S., Kang, K.W., Seu, Y.B. et al. Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells Mech. Ageing Dev., 130 (2009),pp. 179-188
[67]	Kim, K.S., Kim, M.S., Seu, Y.B. et al. Regulation of replicative senescence by insulin-like growth factor-binding protein 3 in human umbilical vein endothelial cells Aging Cell, 6 (2007),pp. 535-545
[68]	Kim, S.A., Lee, K.H., Won, H.Y. et al. Quantitative assessment of aortic elasticity with aging using velocity-vector imaging and its histologic correlation Arterioscler. Thromb. Vasc. Biol., 33 (2013),pp. 1306-1312
[69]	Kovacic, J.C., Moreno, P., Hachinski, V. et al. Cellular senescence, vascular disease, and aging: part 1 of a 2-part review Circulation, 123 (2011),pp. 1650-1660
[70]	Kuliszewski, M.A., Ward, M.R., Kowalewski, J.W. et al. A direct comparison of endothelial progenitor cell dysfunction in rat metabolic syndrome and diabetes Atherosclerosis, 226 (2013),pp. 58-66
[71]	Kumazaki, T., Mitsui, Y. Alterations in transcription factor-binding activities to fibronectin promoter during aging of vascular endothelial cells Mech. Ageing Dev., 88 (1996),pp. 111-124
[72]	Kurz, D.J., Hong, Y., Trivier, E. et al. Fibroblast growth factor-2, but not vascular endothelial growth factor, upregulates telomerase activity in human endothelial cells Arterioscler. Thromb. Vasc. Biol., 23 (2003),pp. 748-754
[73]	Kuznetsova, E., Schliebs, R. Beta-Amyloid, cholinergic transmission, and cerebrovascular system – a developmental study in a mouse model of Alzheimer's disease Curr. Pharm. Des., 19 (2013),pp. 6749-6765
[74]	Langille, B.L., Reidy, M.A., Kline, R.L. Injury and repair of endothelium at sites of flow disturbances near abdominal aortic coarctations in rabbits Arteriosclerosis, 6 (1986),pp. 146-154
[75]	Lee, K.M., Choi, K.H., Ouellette, M.M. Use of exogenous hTERT to immortalize primary human cells Cytotechnology, 45 (2004),pp. 33-38
[76]	Lei, J., Gu, X., Ye, Z. et al. Antiaging effects of simvastatin on vascular endothelial cells Clin. Appl. Thromb. Hemost., 20 (2014),pp. 212-218
[77]	Li, Y., Wang, W.J., Cao, H. et al. Hum. Mol. Genet., 18 (2009),pp. 4897-4904
[78]	Liao, Q., Li, X., Zhou, S. et al. Estrogen treatment inhibits vascular endothelial senescence and asymmetrical dimethylarginine in ovariectomized rabbits J. Cardiovasc. Pharmacol., 57 (2011),pp. 174-182
[79]	Liu, F., Wu, S., Ren, H. et al. Klotho suppresses RIG-I-mediated senescence-associated inflammation Nat. Cell Biol., 13 (2011),pp. 254-262
[80]	Lloyd-Jones, D.M., Evans, J.C., Levy, D. Hypertension in adults across the age spectrum: current outcomes and control in the community JAMA, 294 (2005),pp. 466-472
[81]	Loomans, C.J., de Koning, E.J., Staal, F.J. et al. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes Diabetes, 53 (2004),pp. 195-199
[82]	Maier, J.A., Voulalas, P., Roeder, D. et al. Extension of the life-span of human endothelial cells by an interleukin-1 alpha antisense oligomer Science, 249 (1990),pp. 1570-1574
[83]	Matsushita, H., Chang, E., Glassford, A.J. et al. eNOS activity is reduced in senescent human endothelial cells: preservation by hTERT immortalization Circ. Res., 89 (2001),pp. 793-798
[84]	Menghini, R., Casagrande, V., Cardellini, M. et al. Circulation, 120 (2009),pp. 1524-1532
[85]	Minamino, T., Miyauchi, H., Yoshida, T. et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction Circulation, 105 (2002),pp. 1541-1544
[86]	Minamino, T., Miyauchi, H., Yoshida, T. et al. The role of vascular cell senescence in atherosclerosis: antisenescence as a novel therapeutic strategy for vascular aging Curr. Vasc. Pharmacol., 2 (2004),pp. 141-148
[87]	Minamino, T., Miyauchi, H., Yoshida, T. et al. Vascular cell senescence and vascular aging J. Mol. Cell Cardiol., 36 (2004),pp. 175-183
[88]	Moreau, M.P., Bruse, S.E., Jornsten, R. et al. Chronological changes in microRNA expression in the developing human brain PLoS ONE, 8 (2013),p. e60480
[89]	Morselli, E., Maiuri, M.C., Markaki, M. et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy Cell Death Dis., 1 (2010),p. e10
[90]	Mueller, S.N., Rosen, E.M., Levine, E.M. Cellular senescence in a cloned strain of bovine fetal aortic endothelial cells Science, 207 (1980),pp. 889-891
[91]	Mun, G.I., Lee, S.J., An, S.M. et al. Differential gene expression in young and senescent endothelial cells under static and laminar shear stress conditions Free Radic. Biol. Med., 47 (2009),pp. 291-299
[92]	Niu, S., Matsuda, T. Cell Transplant., 1 (1992),pp. 355-364
[93]	Oeseburg, H., Iusuf, D., van der Harst, P. et al. Bradykinin protects against oxidative stress-induced endothelial cell senescence Hypertension, 53 (2009),pp. 417-422
[94]	Olivieri, F., Lazzarini, R., Recchioni, R. et al. MiR-146a as marker of senescence-associated pro-inflammatory status in cells involved in vascular remodelling Age (Dordr), 35 (2013),pp. 1157-1172
[95]	Olivieri, F., Spazzafumo, L., Santini, G. et al. Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging Mech. Ageing Dev., 133 (2012),pp. 675-685
[96]	Ouellette, M.M., Aisner, D.L., Savre-Train, I. et al. Telomerase activity does not always imply telomere maintenance Biochem. Biophys. Res. Commun., 254 (1999),pp. 795-803
[97]	Patschan, S., Chen, J., Polotskaia, A. et al. Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells Am. J. Physiol. Heart Circ. Physiol., 294 (2008),pp. H1119-H1129
[98]	Patschan, S., Goligorsky, M.S. Autophagy: the missing link between non-enzymatically glycated proteins inducing apoptosis and premature senescence of endothelial cells? Autophagy, 4 (2008),pp. 521-523
[99]	Pavlidis, P., Gouveris, H., Anogeianaki, A. et al. Age-related changes in electrogustometry thresholds, tongue tip vascularization, density, and form of the fungiform papillae in humans Chem. Senses., 38 (2013),pp. 35-43
[100]	Pereira, T.M., Nogueira, B.V., Lima, L.C. et al. Cardiac and vascular changes in elderly atherosclerotic mice: the influence of gender Lipids Health Dis., 9 (2010),p. 87
[101]	Porto, M.L., Lima, L.C., Pereira, T.M. et al. Lipids Health Dis., 10 (2011),p. 155
[102]	Puca, A.A., Daly, M.J., Brewster, S.J. et al. A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4 Proc. Natl. Acad. Sci. USA, 98 (2001),pp. 10505-10508
[103]	Quinn, U., Tomlinson, L.A., Cockcroft, J.R. Arterial stiffness J. RSM Cardiovasc. Dis., 1 (2012)
[104]	Reece, A.S., Hulse, G.K. Reduction in arterial stiffness and vascular age by naltrexone-induced interruption of opiate agonism: a cohort study BMJ Open, 3 (2013)
[105]	Reidy, M.A., Schwartz, S.M. Endothelial injury and regeneration. IV. Endotoxin: a nondenuding injury to aortic endothelium Lab. Invest., 48 (1983),pp. 25-34
[106]	Rippo, M.R., Olivieri, F., Monsurro, V. et al. MitomiRs in human inflamm-aging: a hypothesis involving miR-181a, miR-34a and miR-146a Exp. Gerontol., 56 (2014),pp. 154-163
[107]	Rivard, A., Fabre, J.E., Silver, M. et al. Age-dependent impairment of angiogenesis Circulation, 99 (1999),pp. 111-120
[108]	Rogers, S.C., Zhang, X., Azhar, G. et al. Exposure to high or low glucose levels accelerates the appearance of markers of endothelial cell senescence and induces dysregulation of nitric oxide synthase J. Gerontol. A Biol. Sci. Med. Sci., 68 (2013),pp. 1469-1481
[109]	Ross, R. The pathogenesis of atherosclerosis: a perspective for the 1990s Nature, 362 (1993),pp. 801-809
[110]	Rudner, X.L., Berkowitz, D.E., Booth, J.V. et al. Subtype specific regulation of human vascular alpha(1)-adrenergic receptors by vessel bed and age Circulation, 100 (1999),pp. 2336-2343
[111]	Sadoun, E., Reed, M.J. Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression J. Histochem. Cytochem., 51 (2003),pp. 1119-1130
[112]	Saitsu, H., Nishimura, T., Muramatsu, K. et al. Nat. Genet., 45 (2013),pp. 445-449
[113]	Salpea, P., Russanova, V.R., Hirai, T.H. et al. Postnatal development- and age-related changes in DNA-methylation patterns in the human genome Nucleic Acids Res., 40 (2012),pp. 6477-6494
[114]	Scalera, F., Borlak, J., Beckmann, B. et al. Endogenous nitric oxide synthesis inhibitor asymmetric dimethyl L-arginine accelerates endothelial cell senescence Arterioscler. Thromb. Vasc. Biol., 24 (2004),pp. 1816-1822
[115]	Schachter, F., Faure-Delanef, L., Guenot, F. et al. Nat. Genet., 6 (1994),pp. 29-32
[116]	Schilder, Y.D., Heiss, E.H., Schachner, D. et al. NADPH oxidases 1 and 4 mediate cellular senescence induced by resveratrol in human endothelial cells Free Radic. Biol. Med., 46 (2009),pp. 1598-1606
[117]	Schwartz, S.M., Benditt, E.P. Cell replication in the aortic endothelium: a new method for study of the problem Lab. Invest., 28 (1973),pp. 699-707
[118]	Schwartz, S.M., Benditt, E.P. Clustering of replicating cells in aortic endothelium Proc. Natl. Acad. Sci. USA, 73 (1976),pp. 651-653
[119]	Schwartz, S.M., Benditt, E.P. Aortic endothelial cell replication. I. Effects of age and hypertension in the rat Circ. Res., 41 (1977),pp. 248-255
[120]	Schwartz, S.M., Haudenschild, C.C., Eddy, E.M. Endothelial regeneration. I. Quantitative analysis of initial stages of endothelial regeneration in rat aortic intima Lab. Invest., 38 (1978),pp. 568-580
[121]	Shan, H., Bai, X., Chen, X. Angiotensin II induces endothelial cell senescence via the activation of mitogen-activated protein kinases Cell Biochem. Funct., 26 (2008),pp. 459-466
[122]	Shan, H., Guo, D., Li, X. et al. From autophagy to senescence and apoptosis in Angiotensin II-treated vascular endothelial cells APMIS (2014)
[123]	Shelton, D.N., Chang, E., Whittier, P.S. et al. Microarray analysis of replicative senescence Curr. Biol., 9 (1999),pp. 939-945
[124]	Shen, X.H., Xu, S.J., Jin, C.Y. et al. Int. Immunopharmacol., 16 (2013),pp. 261-267
[125]	Soerensen, M., Dato, S., Tan, Q. et al. Age (Dordr), 35 (2013),pp. 487-500
[126]	Soltis, E.E. Effect of age on blood pressure and membrane-dependent vascular responses in the rat Circ. Res., 61 (1987),pp. 889-897
[127]	Stein, J.H. Carotid intima-media thickness and vascular age: you are only as old as your arteries look J. Am. Soc. Echocardiogr., 17 (2004),pp. 686-689
[128]	Stoner, L., Young, J.M., Fryer, S. Assessments of arterial stiffness and endothelial function using pulse wave analysis Int. J. Vasc. Med., 2012 (2012),p. 903107
[129]	Swim, H.E., Parker, R.F. Culture characteristics of human fibroblasts propagated serially Am. J. Hyg., 66 (1957),pp. 235-243
[130]	Taddei, S., Virdis, A., Mattei, P. et al. Hypertension causes premature aging of endothelial function in humans Hypertension, 29 (1997),pp. 736-743
[131]	Togliatto, G., Trombetta, A., Dentelli, P. et al. Unacylated ghrelin rescues endothelial progenitor cell function in individuals with type 2 diabetes Diabetes, 59 (2010),pp. 1016-1025
[132]	Torisu, T., Torisu, K., Lee, I.H. et al. Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor Nat. Med., 19 (2013),pp. 1281-1287
[133]	Tsuzuki, M. Bone marrow-derived cells are not involved in reendothelialized endothelium as endothelial cells after simple endothelial denudation in mice Basic Res. Cardiol., 104 (2009),pp. 601-611
[134]	Unterluggauer, H., Hutter, E., Voglauer, R. et al. Biogerontology, 8 (2007),pp. 383-397
[135]	Vamos, Z., Cseplo, P., Ivic, I. et al. Age determines the magnitudes of angiotensin II-induced contractions, mRNA, and protein expression of angiotensin type 1 receptors in rat carotid arteries J. Gerontol. A Biol. Sci. Med. Sci., 69 (2013),pp. 519-526
[136]	Vanhoutte, P.M. Aging and vascular responsiveness J. Cardiovasc. Pharmacol., 12 (1988),pp. S11-S19
[137]	Vasa, M., Breitschopf, K., Zeiher, A.M. et al. Nitric oxide activates telomerase and delays endothelial cell senescence Circ. Res., 87 (2000),pp. 540-542
[138]	Vasa-Nicotera, M., Chen, H., Tucci, P. et al. miR-146a is modulated in human endothelial cell with aging Atherosclerosis, 217 (2011),pp. 326-330
[139]	Veitonmaki, N., Fuxe, J., Hultdin, M. et al. Immortalization of bovine capillary endothelial cells by hTERT alone involves inactivation of endogenous p16INK4A/pRb FASEB J., 17 (2003),pp. 764-766
[140]	Venable, M.E., Yin, X. Ceramide induces endothelial cell senescence Cell Biochem. Funct., 27 (2009),pp. 547-551
[141]	Villa-Bellosta, R., Rivera-Torres, J., Osorio, F.G. et al. Defective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of Hutchinson-Gilford progeria syndrome that is ameliorated on pyrophosphate treatment Circulation, 127 (2013),pp. 2442-2451
[142]	Virmani, R., Avolio, A.P., Mergner, W.J. et al. Effect of aging on aortic morphology in populations with high and low prevalence of hypertension and atherosclerosis. Comparison between occidental and Chinese communities Am. J. Pathol., 139 (1991),pp. 1119-1129
[143]	Walter, D.H., Rittig, K., Bahlmann, F.H. et al. Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells Circulation, 105 (2002),pp. 3017-3024
[144]	Wang, C.J., Hu, C.P., Xu, K.P. et al. Effects of selaginellin on homocysteine-induced senescence in human umbilical vein endothelial cells J. Cardiovasc. Pharmacol., 55 (2010),pp. 560-566
[145]	Wang, J.C., Bennett, M. Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence Circ. Res., 111 (2012),pp. 245-259
[146]	Weber, T., Ammer, M., Rammer, M. et al. Noninvasive determination of carotid-femoral pulse wave velocity depends critically on assessment of travel distance: a comparison with invasive measurement J. Hypertens., 27 (2009),pp. 1624-1630
[147]	Werner, N., Junk, S., Laufs, U. et al. Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury Circ. Res., 93 (2003),pp. e17-24
[148]	West, J., Widschwendter, M., Teschendorff, A.E. Distinctive topology of age-associated epigenetic drift in the human interactome Proc. Natl. Acad. Sci. USA, 110 (2013),pp. 14138-14143
[149]	Willcox, B.J., Donlon, T.A., He, Q. et al. Proc. Natl. Acad. Sci. USA, 105 (2008),pp. 13987-13992
[150]	Xu, D., Neville, R., Finkel, T. Homocysteine accelerates endothelial cell senescence FEBS Lett., 470 (2000),pp. 20-24
[151]	Xu, Q., Zhang, Z., Davison, F. et al. Circ. Res., 93 (2003),pp. e76-e86
[152]	Yang, J., Chang, E., Cherry, A.M. et al. Human endothelial cell life extension by telomerase expression J. Biol. Chem., 274 (1999),pp. 26141-26148
[153]	Yang, Z., Chen, L., Su, C. et al. Impaired endothelial progenitor cell activity is associated with reduced arterial elasticity in patients with essential hypertension Clin. Exp. Hypertens., 32 (2010),pp. 444-452
[154]	Yeh, E.T. CRP as a mediator of disease Circulation, 109 (2004),pp. II11-14
[155]	Yokoi, T., Fukuo, K., Yasuda, O. et al. Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells Diabetes, 55 (2006),pp. 1660-1665
[156]	Young, A.R., Narita, M., Ferreira, M. et al. Autophagy mediates the mitotic senescence transition Genes Dev., 23 (2009),pp. 798-803
[157]	Young, A.T., Lakey, J.R., Murray, A.G. et al. Transplant Proc., 35 (2003),pp. 2483-2485
[158]	Zhang, L., Connelly, J.J., Peppel, K. et al. Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies Hum. Mol. Genet., 19 (2010),pp. 2754-2766
[159]	Zhang, Y., Herbert, B.S., Rajashekhar, G. et al. FASEB J., 23 (2009),pp. 1358-1365
[160]	Zhao, L., Yang, F., Xu, K. et al. Common genetic variants of the beta 2-adrenergic receptor affect its translational efficiency and are associated with human longevity Aging Cell, 11 (2012),pp. 1094-1101
[161]	Zhou, S., Chen, H.Z., Wan, Y.Z. et al. Repression of P66Shc expression by SIRT1 contributes to the prevention of hyperglycemia-induced endothelial dysfunction Circ. Res., 109 (2011),pp. 639-648