Aging of the Vasculature and Related Systems

  • José Marín-García
  • Michael J. Goldenthal
  • Gordon W. Moe


Vascular Smooth Muscle Cell Arterial Stiffness Cellular Senescence Arterioscler Thromb Vasc Biol Aortic Stiffness 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Najjar SS, Scuteri A, Lakatta EG. Arterial aging: is it an immutable cardiovascular risk factor? Hypertension 2005;46:454–462PubMedGoogle Scholar
  2. 2.
    Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 1993;73:413–467PubMedGoogle Scholar
  3. 3.
    Nagai Y, Metter EJ, Earley CJ, Kemper MK, Becker LC, Lakatta EG, Fleg JL. Increased carotid artery intimal-medial thickness in asymptomatic older subjects with exercise-induced myocardial ischemia. Circulation 1998;98:1504–1509PubMedGoogle Scholar
  4. 4.
    Virmani R, Avolio AP, Mergner WJ, Robinowitz M, Herderick EE, Cornhill JF, Guo SY, Liu TH, Ou DY, O’Rourke M. 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 1991;139:1119–1129PubMedGoogle Scholar
  5. 5.
    Li Z, Froehlich J, Galis ZS, Lakatta EG. Increased expression of matrix metalloproteinase-2 in the thickened intima of aged rats. Hypertension 1999;33:116–123PubMedGoogle Scholar
  6. 6.
    Asai K, Kudej RK, Shen YT, Yang GP, Takagi G, Kudej AB, Geng YJ, Sato N, Nazareno JB, Vatner DE, Natividad F, Bishop SP, Vatner SF. Peripheral vascular endothelial dysfunction and apoptosis in old monkeys. Arterioscler Thromb Vasc Biol 2000;20:1493–1499PubMedGoogle Scholar
  7. 7.
    Orlandi A, Marcellini M, Spagnoli LG. Aging influences development and progression of early aortic atherosclerotic lesions in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol 2000;20:1123–1136PubMedGoogle Scholar
  8. 8.
    Spinetti G, Wang M, Monticone R, Zhang J, Zhao D, Lakatta EG. Rat aortic MCP-1 and its receptor CCR2 increase with age and alter vascular smooth muscle cell function. Arterioscler Thromb Vasc Biol 2004;24:1397–1402PubMedGoogle Scholar
  9. 9.
    Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2–/–mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998;394:894–897PubMedGoogle Scholar
  10. 10.
    Wang M, Lakatta EG. Altered regulation of matrix metalloproteinase-2 in aortic remodeling during aging. Hypertension 2002;39:865–887PubMedGoogle Scholar
  11. 11.
    Wang M, Takagi G, Asai K, Resuello RG, Natividad FF, Vatner DE, Vatner SF, Lakatta EG. Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension 2003;41:1308–1316PubMedGoogle Scholar
  12. 12.
    Li Z, Cheng H, Lederer WJ, Froehlich J, Lakatta EG. Enhanced proliferation and migration and altered cytoskeletal proteins in early passage smooth muscle cells from young and old rat aortic explants. Exp Mol Pathol 1997;64:1–11PubMedGoogle Scholar
  13. 13.
    Hariri RJ, Hajjar DP, Coletti D, Alonso DR, Weksler ME, Rabellino E. Aging and arteriosclerosis. Cell cycle kinetics of young and old arterial smooth muscle cells. Am J Pathol 1988;131:132–136PubMedGoogle Scholar
  14. 14.
    Torella D, Leosco D, Indolfi C, Curcio A, Coppola C, Ellison GM, Russo VG, Torella M, Li Volti G, Rengo F, Chiariello M. Aging exacerbates negative remodeling and impairs endothelial regeneration after balloon injury. Am J Physiol Heart Circ Physiol 2004;287:H2850–H2860Google Scholar
  15. 15.
    Hofmann CS, Wang X, Sullivan CP, Toselli P, Stone PJ, McLean SE, Mecham RP, Schreiber BM, Sonenshein GE. B-Myb represses elastin gene expression in aortic smooth muscle cells. J Biol Chem 2005;280: 7694–7701PubMedGoogle Scholar
  16. 16.
    Duca L, Floquet N, Alix AJ, Haye B, Debelle L. Elastin as a matrikine. Crit Rev Oncol Hematol 2004;49:235–244PubMedGoogle Scholar
  17. 17.
    Vaitkevicius PV, Lane M, Spurgeon H, Ingram DK, Roth GS, Egan JJ, Vasan S, Wagle DR, Ulrich P, Brines M, Wuerth JP, Cerami A, Lakatta EG. A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. Proc Natl Acad Sci USA 2001;98:1171–1175PubMedGoogle Scholar
  18. 18.
    O’Rourke MF, Nichols WW. Aortic diameter, aortic stiffness, and wave reflection increase with age and isolated systolic hypertension. Hypertension 2005;45:652–658PubMedGoogle Scholar
  19. 19.
    Susic D, Varagic J, Ahn J, Frohlich ED. Collagen cross-link breakers: a beginning of a new era in the treatment of cardiovascular changes associated with aging, diabetes, and hypertension. Curr Drug Targets Cardiovasc Haematol Disord 2004;4:97–101PubMedGoogle Scholar
  20. 20.
    Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S. Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens 2004;17:23S–30SPubMedGoogle Scholar
  21. 21.
    Franklin SS, Gustin WIV, Wong ND, Larson MG, Weber MA, Kannel WB, Levy D. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation 1997;96:308–315Google Scholar
  22. 22.
    Wilkinson IB, Franklin SS, Hall IR, Tyrrell S, Cockcroft JR. Pressure amplification explains why pulse pressure is unrelated to risk in young subjects. Hypertension 2001;38:1461–1466PubMedGoogle Scholar
  23. 23.
    Benetos A, Laurent S, Hoeks AP, Boutouyrie PH, Safar ME. Arterial alterations with aging and high blood pressure. A noninvasive study of carotid and femoral arteries. Arterioscler Thromb 1993;13:90–97PubMedGoogle Scholar
  24. 24.
    Lieber SC, Aubry N, Pain J, Diaz G, Kim SJ, Vatner SF. Aging increases stiffness of cardiac myocytes measured by atomic force microscopy nanoindentation. Am J Physiol Heart Circ Physiol 2004;287:H645–H651PubMedGoogle Scholar
  25. 25.
    Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension 2005;45:1050–1055PubMedGoogle Scholar
  26. 26.
    Benetos A, Topouchian J, Ricard S, Gautier S, Bonnardeaux A, Asmar R, Poirier O, Soubrier F, Safar M, Cambien F. Influence of angiotensin II type 1 receptor polymorphism on aortic stiffness in never-treated hypertensive patients. Hypertension 1995;26:44–47PubMedGoogle Scholar
  27. 27.
    Lajemi M, Labat C, Gautier S, Lacolley P, Safar M, Asmar R, Cambien F, Benetos A. Angiotensin II type 1 receptor-153A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects. J Hypertens 2001;19:407–413PubMedGoogle Scholar
  28. 28.
    Mattace-Raso FU, van der Cammen TJ, Sayed-Tabatabaei FA, van Popele NM, Asmar R, Schalekamp MA, Hofman A, van Duijn CM, Witteman JC. Angiotensin-converting enzyme gene polymorphism and common carotid stiffness. The Rotterdam study. Atherosclerosis 2004;174:121–126Google Scholar
  29. 29.
    Bozec E, Lacolley P, Bergaya S, Boutouyrie P, Meneton P, Herisse-Legrand M, Boulanger CM, Alhenc-Gelas F, Kim HS, Laurent S, Dabire H. Arterial stiffness and angiotensinogen gene in hypertensive patients and mutant mice. J Hypertens 2004;22:1299–1307PubMedGoogle Scholar
  30. 30.
    Pojoga L, Gautier S, Blanc H, Guyene TT, Poirier O, Cambien F, Benetos A. Genetic determination of plasma aldosterone levels in essential hypertension. Am J Hypertens 1998;11:856–860PubMedGoogle Scholar
  31. 31.
    Wojciechowska W, Staessen JA, Stolarz K, Nawrot T, Filipovsky J, Ticha M, Bianchi G, Brand E, Cwynar M, Grodzicki T, Kuznetsova T, Struijker-Boudier HA, Svobodova V, Thijs L, Van Bortel LM, Kawecka-Jaszcz K. European Project on Genes in Hypertension (EPOGH) Investigators. Association of peripheral and central arterial wave reflections with the CYP11B2 -344C allele and sodium excretion. J Hypertens 2004;22: 2311–2319PubMedGoogle Scholar
  32. 32.
    Safar ME, Cattan V, Lacolley P, Nzietchueng R, Labat C, Lajemi M, de Luca N, Benetos A. Aldosterone synthase gene polymorphism, stroke volume and age-related changes in aortic pulse wave velocity in subjects with hypertension. J Hypertens 2005;23:1159–1166Google Scholar
  33. 33.
    Hanon O, Luong V, Mourad JJ, Bortolotto LA, Jeunemaitre X, Girerd X. Aging, carotid artery distensibility, and the Ser422Gly elastin gene polymorphism in humans. Hypertension 2001;38:1185–1189PubMedGoogle Scholar
  34. 34.
    Medley TL, Cole TJ, Gatzka CD, Wang WY, Dart AM, Kingwell BA. Fibrillin-1 genotype is associated with aortic stiffness and disease severity in patients with coronary artery disease. Circulation 2002;105:810–815PubMedGoogle Scholar
  35. 35.
    Powell JT, Turner RJ, Sian M, Debasso R, Lanne T. Influence of fibrillin-1 genotype on the aortic stiffness in men. J Appl Physiol 2005;99:1036–1040PubMedGoogle Scholar
  36. 36.
    Medley TL, Kingwell BA, Gatzka CD, Pillay P, Cole TJ. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res 2003;92: 1254–1261PubMedGoogle Scholar
  37. 37.
    Medley TL, Cole TJ, Dart AM, Gatzka CD, Kingwell BA. Matrix metalloproteinase-9 genotype influences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vasc Biol 2004;24:1479–1484PubMedGoogle Scholar
  38. 38.
    Yasmin, McEniery CM, O’Shaughnessy KM, Harnett P, Arshad A, Wallace S, Maki-Petaja K, McDonnell B, Ashby MJ, Brown J, Cockcroft JR, Wilkinson IB. Variation in the human matrix metalloproteinase-9 gene is associated with arterial stiffness in healthy individuals. Arterioscler Thromb Vasc Biol 2006;26:1799–1805Google Scholar
  39. 39.
    Chen W, Srinivasan SR, Bond MG, Tang R, Urbina EM, Li S, Boerwinkle E, Berenson GS. Nitric oxide synthase gene polymorphism (G894T) influences arterial stiffness in adults: The Bogalusa Heart Study. Am J Hypertens 2004;17:553–559PubMedGoogle Scholar
  40. 40.
    Lajemi M, Gautier S, Poirier O, Baguet JP, Mimran A, Gosse P, Hanon O, Labat C, Cambien F, Benetos A. Endothelin gene variants and aortic and cardiac structure in never-treated hypertensives. Am J Hypertens 2001;14:755–760PubMedGoogle Scholar
  41. 41.
    Nurnberger J, Opazo Saez A, Mitchell A, Buhrmann S, Wenzel RR, Siffert W, Philipp T, Schafers RF. The T-allele of the C825T polymorphism is associated with higher arterial stiffness in young healthy males. J Hum Hypertens 2004;18:267–271PubMedGoogle Scholar
  42. 42.
    Iemitsu M, Maeda S, Otsuki T, Sugawara J, Tanabe T, Jesmin S, Kuno S, Ajisaka R, Miyauchi T, Matsuda M. Polymorphism in endothelin-related genes limits exercise-induced decreases in arterial stiffness in older subjects. Hypertension 2006;47:928–936PubMedGoogle Scholar
  43. 43.
    Durier S, Fassot C, Laurent S, Boutouyrie P, Couetil JP, Fine E, Lacolley P, Dzau VJ, Pratt RE. Physiological genomics of human arteries: quantitative relationship between gene expression and arterial stiffness. Circulation 2003;108:1845–1851PubMedGoogle Scholar
  44. 44.
    Saward L, Zahradka P. Angiotensin II activates phosphatidylinositol 3-kinase in vascular smooth muscle cells. Circ Res 1997;81:249–257PubMedGoogle Scholar
  45. 45.
    Quignard JF, Mironneau J, Carricaburu V, Fournier B, Babich A, Numberg B, Mironneau C, Macrez N. Phosphoinositide 3-kinase gamma mediates angiotensin II–induced stimulation of L-type calcium channels in vascular myocytes. J Biol Chem 2001;276:32545–32551PubMedGoogle Scholar
  46. 46.
    Shen TL, Guan JL. Differential regulation of cell migration and cell cycle progression by FAK complexes with Src, PI3K, Grb7 and Grb2 in focal contacts. FEBS Lett 2001;499:176–181PubMedGoogle Scholar
  47. 47.
    Zheng XL, Renaux B, Hollenberg MD. Parallel contractile signal transduction pathways activated by receptors for thrombin and epidermal growth factor–urogastrone in guinea pig gastric smooth muscle: blockade by inhibitors of mitogen-activated protein kinase-kinase and phosphatidyl inositol 3’-kinase. J Pharmacol Exp Ther 1998;285:325–334PubMedGoogle Scholar
  48. 48.
    Maeda S, Iemitsu M, Miyauchi T, Kuno S, Matsuda M, Tanaka H. Aortic stiffness and aerobic exercise: mechanistic insight from microarray analyses. Med Sci Sports Exerc 2005;37:1710–1716PubMedGoogle Scholar
  49. 49.
    Wilkinson IB, Franklin SS, Cockcroft JR. Nitric oxide and the regulation of large artery stiffness: from physiology to pharmacology. Hypertension 2004;44:112–116PubMedGoogle Scholar
  50. 50.
    Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 1994;24:471–476PubMedGoogle Scholar
  51. 51.
    Gerhard M, Roddy MA, Creager SJ, Creager MA. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension 1996;27:849–853PubMedGoogle Scholar
  52. 52.
    McEniery CM, Wallace S, Mackenzie IS, McDonnell B, Yasmin, Newby DE, Cockcroft JR, Wilkinson IB. Endothelial function is associated with pulse pressure, pulse wave velocity, and augmentation index in healthy humans. Hypertension 2006;48:602–608Google Scholar
  53. 53.
    Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res 2005;66:286–294PubMedGoogle Scholar
  54. 54.
    Goligorsky MS. Endothelial cell dysfunction: can’t live with it, how to live without it. Am J Physiol Renal Physiol 2005;288:F871–F880PubMedGoogle Scholar
  55. 55.
    Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 2000;113:3613–3622PubMedGoogle Scholar
  56. 56.
    Foreman KE, Tang J. Molecular mechanisms of replicative senescence in endothelial cells. Exp Geronto 2003;38:1251–1257Google Scholar
  57. 57.
    Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, Magner M, Asahara T, Isner JM. Age-dependent impairment of angiogenesis. Circulation 1999;99:111–120PubMedGoogle Scholar
  58. 58.
    Yang J, Chang E, Cherry AM, Bangs CD, Oei Y, Bodnar A, Bronstein A, Chiu CP, Herron GS. Human endothelial cell life extension by telomerase expression. J Biol Chem 1999;274:26141–26148PubMedGoogle Scholar
  59. 59.
    Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–967Google Scholar
  60. 60.
    Werner N, Nickenig G. Clinical and therapeutical implications of EPC biology in atherosclerosis. J Cell Mol Med 2006;10:318–332PubMedGoogle Scholar
  61. 61.
    Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593–600PubMedGoogle Scholar
  62. 62.
    Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001;89:e1–e7PubMedGoogle Scholar
  63. 63.
    Edelberg JM, Tang L, Hattori K, Lyden D, Rafii S. Young adult bone marrow-derived endothelial precursor cells restore aging-impaired cardiac angiogenic function. Circ Res 2002;90:E89–E93PubMedGoogle Scholar
  64. 64.
    Buys CH. Telomeres, telomerase, and cancer. N Engl J Med 2000;342:1282–1283PubMedGoogle Scholar
  65. 65.
    Aviv H, Khan MY, Skurnick J, Okuda K, Kimura M, Gardner J, Priolo L, Aviv A. Age dependent aneuploidy and telomere length of the human vascular endothelium. Atherosclerosis 2001;159:281–287PubMedGoogle Scholar
  66. 66.
    Chang E, Harley CB. Telomere length and replicative aging in human vascular tissues. Proc Natl Acad Sci USA 1995;92:11190–11194PubMedGoogle Scholar
  67. 67.
    Minamino T, Kourembanas S. Mechanisms of telomerase induction during vascular smooth muscle cell proliferation. Circ Res 2001;89:237–243PubMedGoogle Scholar
  68. 68.
    Hsiao R, Sharma HW, Ramakrishnan S, Keith E, Narayanan R. Telomerase activity in normal human endothelial cells. Anticancer Res 1997;17:827–832PubMedGoogle Scholar
  69. 69.
    Minamino T, Mitsialis SA, Kourembanas S. Hypoxia extends the life span of vascular smooth muscle cells through telomerase activation. Mol Cell Biol 2001;21:3336–3342PubMedGoogle Scholar
  70. 70.
    Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I. Endothelial cell senescence in human atherosclerosis:role of telomere in endothelial dysfunction. Circulation 2002;105:1541–1544PubMedGoogle Scholar
  71. 71.
    Young AT, Lakey JR, Murray AG, Mullen JC, Moore RB. In vitro senescence occurring in normal human endothelial cells can be rescued by ectopic telomerase activity. Transplant Proc 2003;35:2483–2485PubMedGoogle Scholar
  72. 72.
    Matsushita H, Chang E, Glassford AJ, Cooke JP, Chiu CP, Tsao PS. eNOS activity is reduced in senescent human endothelial cells: preservation by hTERT immortalization. Circ Res 2001;89:793–798PubMedGoogle Scholar
  73. 73.
    von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci 2002;27:339–344Google Scholar
  74. 74.
    Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, Erusalimsky JD. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J Cell Sci 2004;117:2417–2426PubMedGoogle Scholar
  75. 75.
    Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, Dimmeler S. Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. Circ Res 2004;94:768–775PubMedGoogle Scholar
  76. 76.
    Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci USA 2004;101:17312–17315PubMedGoogle Scholar
  77. 77.
    Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Cell aging in relation to stress arousal and cardiovascular disease risk factors. Psychoneuroendocrinology 2006;31:277–287PubMedGoogle Scholar
  78. 78.
    Ogami M, Ikura Y, Ohsawa M, Matsuo T, Kayo S, Yoshimi N, Hai E, Shirai N, Ehara S, Komatsu R, Naruko T, Ueda M. Telomere shortening in human coronary artery diseases. Arterioscler Thromb Vasc Biol 2004;24:546–550PubMedGoogle Scholar
  79. 79.
    Smogorzewska A, de Lange T. Different telomere damage signaling pathways in human and mouse cells. EMBO J 2002;21:4338–4348PubMedGoogle Scholar
  80. 80.
    Lechel A, Satyanarayana A, Ju Z, Plentz RR, Schaetzlein S, Rudolph C, Wilkens L, Wiemann SU, Saretzki G, Malek NP, Manns MP, Buer J, Rudolph KL. The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo. EMBO Rep 2005;6:275–281PubMedGoogle Scholar
  81. 81.
    Yang Q, Zheng YL, Harris CC. POT1 and TRF2 cooperate to maintain telomeric integrity. Mol Cell Biol 2005;25:1070–1080PubMedGoogle Scholar
  82. 82.
    Serrano M, Blasco MA. Putting the stress on senescence. Curr Opin Cell Biol 2001;13:748–753PubMedGoogle Scholar
  83. 83.
    Toussaint O, Medrano EE, von Zglinicki T. Cellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. Exp Gerontol 2000;35:927–945PubMedGoogle Scholar
  84. 84.
    Drayton S, Peters G. Immortalisation and transformation revisited. Curr Opin Genet Dev 2002;12:98–104PubMedGoogle Scholar
  85. 85.
    Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16 INK4a. Cell 1997;88:593–602PubMedGoogle Scholar
  86. 86.
    Dimri GP, Itahana K, Acosta M, Campisi J. Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14(ARF) tumor suppressor. Mol Cell Biol 2000;20:273–285PubMedGoogle Scholar
  87. 87.
    Minamino T, Yoshida T, Tateno K, Miyauchi H, Zou Y, Toko H, Komuro I. Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis. Circulation 2003;108:2264–2269PubMedGoogle Scholar
  88. 88.
    Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 1998;12:3008–3019Google Scholar
  89. 89.
    Wang W, Chen JX, Liao R, Deng Q, Zhou JJ, Huang S, Sun P. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol 2002;22:3389–3403PubMedGoogle Scholar
  90. 90.
    Chen J, Brodsky SV, Goligorsky DM, Hampel DJ, Li H, Gross SS, Goligorsky MS. Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells. Circ Res 2002;90:1290–1298PubMedGoogle Scholar
  91. 91.
    Ben-Porath I, Weinberg RA. When cells get stressed: an integrative view of cellular senescence. J Clin Invest 2004;113: 8–13PubMedGoogle Scholar
  92. 92.
    Narita M, Nunez S, Heard E, Lin AW, Hearn SA, Spector DL. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003;113:703–716PubMedGoogle Scholar
  93. 93.
    Kulju KS, Lehman JM. Increased p53 protein associated with aging in human diploid fibroblasts. Experimental Cell Research 1995;217:336–345PubMedGoogle Scholar
  94. 94.
    Wahl GM, Carr AM. The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nature Cell Biology 2001;3:E277–E286PubMedGoogle Scholar
  95. 95.
    d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP. A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003;426:194–198PubMedGoogle Scholar
  96. 96.
    Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16 INK4a. Cell 1997;88:593–602PubMedGoogle Scholar
  97. 97.
    Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE. Ink4a/Arf expression is a biomarker of aging. J Clin Invest 2004;114:1299–1307PubMedGoogle Scholar
  98. 98.
    Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci USA 1996;93:13742–13747PubMedGoogle Scholar
  99. 99.
    Malumbres M, Perez De Castro I, Hernandez MI, Jimenez M, Corral T, Pellicer A. Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15(INK4b). Mol Cell Biol 2000;20:2915–2925Google Scholar
  100. 100.
    Robertson KD, Jones PA. The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Mol Cell Biol 1998;18:6457–6473PubMedGoogle Scholar
  101. 101.
    Freedman DA, Folkman J. CDK2 translational down-regulation during endothelial senescence. Exp Cell Res 2005;307:118–130PubMedGoogle Scholar
  102. 102.
    Tang J, Gordon GM, Nickoloff BJ, Foreman KE. The helix-loop-helix protein id-1 delays onset of replicative senescence in human endothelial cells. Lab Invest 2002;82:1073–1079PubMedGoogle Scholar
  103. 103.
    Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 2003;22:4212–4222PubMedGoogle Scholar
  104. 104.
    Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003;113:703–716PubMedGoogle Scholar
  105. 105.
    Sato I, Morita I, Kaji K, Ikeda M, Nagao M, Murota S. Reduction of nitric oxide producing activity associated with in vitro aging in cultured human umbilical vein endothelial cell. Biochem Biophys Res Commun 1993;195:1070–1076PubMedGoogle Scholar
  106. 106.
    Deshpande SS, Qi B, Park YC, Irani K. Constitutive activation of rac1 results in mitochondrial oxidative stress and induces premature endothelial cell senescence. Arterioscler Thromb Vasc Biol 2003;23:e1–e6PubMedGoogle Scholar
  107. 107.
    Unterluggauer H, Hampel B, Zwerschke W, Jansen-Durr P. Senescence-associated cell death of human endothelial cells: the role of oxidative stress. Exp Gerontol 2003;38:1149–1160PubMedGoogle Scholar
  108. 108.
    van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callender M, Erusalimsky JD, Quaschning T, Malinski T, Gygi D, Ullrich V, Luscher TF. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 2000;192:1731–1744PubMedGoogle Scholar
  109. 109.
    Nakajima M, Hashimoto M, Wang F, Yamanaga K, Nakamura N, Uchida T, Yamanouchi K. Aging decreases the production of PGI2 in rat aortic endothelial cells. Exp Gerontol 1997;32:685–693PubMedGoogle Scholar
  110. 110.
    Sato I, Kaji K, Morita I, Nagao M, Murota S. Augmentation of endothelin-1, prostacyclin and thromboxane A2 secretion associated with in vitro ageing in cultured human umbilical vein endothelial cells. Mech Ageing Dev 1993;71:73–84PubMedGoogle Scholar
  111. 111.
    Neubert K, Haberland A, Kruse I, Wirth M, Schimke I. The ratio of formation of prostacyclin/thromboxane A2 in HUVEC decreased in each subsequent passage. Prostaglandins 1997;54:447–462PubMedGoogle Scholar
  112. 112.
    Comi P, Chiaramonte R, Maier JA. Senescence-dependent regulation of type 1 plasminogen activator inhibitor in human vascular endothelial cells. Exp Cell Res 1995;219:304–308PubMedGoogle Scholar
  113. 113.
    West MD, Shay JW, Wright WE, Linskens MH. Altered expression of plasminogen activator and plasminogen activator inhibitor during cellular senescence. Exp Gerontol 1996;31:175–193PubMedGoogle Scholar
  114. 114.
    Maier JA, Statuto M, Ragnotti G. Senescence stimulates U937-endothelial cell interactions. Exp Cell Res 1993;208:270–274PubMedGoogle Scholar
  115. 115.
    Kalashnik L, Bridgeman CJ, King AR, Francis SE, Mikhalovsky S, Wallis C, Denyer SP, Crossman D, Faragher RG. A cell kinetic analysis of human umbilical vein endothelial cells. Mech Ageing Dev 2000;120:23–32PubMedGoogle Scholar
  116. 116.
    Wagner M, Hampel B, Bernhard D, Hala M, Zwerschke W, Jansen-Durr P. Replicative senescence of human endothelial cells in vitro involves G1 arrest, polyploidization and senescence-associated apoptosis. Exp Gerontol 2001;36:1327–1347PubMedGoogle Scholar
  117. 117.
    Wang, E. Senescent human fibroblasts resist programmed cell death, and failure to suppress Bcl2 is involved. Cancer Res 1995;55:2284–2292PubMedGoogle Scholar
  118. 118.
    Zhang J, Patel JM, Block ER. Enhanced apoptosis in prolonged cultures of senescent porcine pulmonary artery endothelial cells. Mech Ageing Dev 2002;123:613–625PubMedGoogle Scholar
  119. 119.
    Hampel B, Fortschegger K, Ressler S, Chang MW, Unterluggauer H, Breitwieser A, Sommergruber W, Fitzky B, Lepperdinger G, Jansen-Durr P, Voglauer R, Grillari J. Increased expression of extracellular proteins as a hallmark of human endothelial cell in vitro senescence. Exp Gerontol 2006;41:474–481PubMedGoogle Scholar
  120. 120.
    Cristofalo VJ, Lorenzini A, Allen RG, Torres C, Tresini M. Replicative senescence: a critical review. Mech Ageing Dev 2004;125:827–848PubMedGoogle Scholar
  121. 121.
    Minamino T, Komuro I. Vascular cell senescence: contribution to atherosclerosis. Circ Res 2007;100:15–26PubMedGoogle Scholar
  122. 122.
    Erusalimsky JD, Kurz DJ. Cellular senescence in vivo: its relevance in ageing and cardiovascular disease. Exp Gerontol 2005;40:634–642PubMedGoogle Scholar
  123. 123.
    Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 1997;91:25–34PubMedGoogle Scholar
  124. 124.
    Satyanarayana A, Wiemann SU, Buer J, Lauber J, Dittmar KE, Wustefeld T, Blasco MA, Manns MP, Rudolph KL. Telomere shortening impairs organ regeneration by inhibiting cell cycle re-entry of a subpopulation of cells. EMBO J 2003;22:4003–4013PubMedGoogle Scholar
  125. 125.
    Lee HW, Blasco MA, Gottlieb GJ, Horner JW, Greider RA, DePinho RA. Essential role of mouse telomerase in highly proliferative organs. Nature 1998;392:569–574Google Scholar
  126. 126.
    Franco S, Segura I, Riese HH, Blasco MA. Decreased B16F10 melanoma growth and impaired vascularization in telomerase-deficient mice with critically short telomeres. Cancer Res 2002;62:552–559PubMedGoogle Scholar
  127. 127.
    Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J. Aging and genome maintenance: lessons from the mouse? Science 2003;299:1355–1359Google Scholar
  128. 128.
    Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW, Harley CB. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 1992;89:10114–10118PubMedGoogle Scholar
  129. 129.
    Marciniak RA, Johnson FB, Guarente L. Dyskeratosis congenita, telomeres and human ageing. Trends Genet 2000;16:193–195PubMedGoogle Scholar
  130. 130.
    Tchirkov A, Lansdorp PM. Role of oxidative stress in telomere shortening in cultured fibroblasts from normal individuals and patients with ataxia-telangiectasia, Hum Mol Genet 2003:12:227–232PubMedGoogle Scholar
  131. 131.
    Crabbe L, Verdun RE, Haggblom CI, Karlseder J. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 2004;306:1951–1953PubMedGoogle Scholar
  132. 132.
    Hamilton CA, Brosnan MJ, McIntyre M, Graham D, Dominiczak AF. Superoxide excess in hypertension and aging: a common cause of endothelial dysfunction. Hypertension 2001;37:529–534PubMedGoogle Scholar
  133. 133.
    Brandes RP, Barton M, Philippens KM, Schweitzer G, Mugge A. Endothelial-derived superoxide anions in pig coronary arteries: evidence from lucigenin chemiluminescence and histochemical techniques. J Physiol 1997;500:331–342PubMedGoogle Scholar
  134. 134.
    Gorlach A, Brandes RP, Nguyen K, Amidi M, Dehghani F, Busse R. A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall. Circ Res 2000;87:26–32PubMedGoogle Scholar
  135. 135.
    Jung O, Schreiber JG, Geiger H, Pedrazzini T, Busse R, Brandes RP. gp91phox-containing NADPH oxidase mediates endothelial dysfunction in renovascular hypertension. Circulation 2004;109:1795–1801PubMedGoogle Scholar
  136. 136.
    Burns EM, Kruckeberg TW, Comerford LE, Buschmann MT. Thinning of capillary walls and declining numbers of endothelial mitochondria in the cerebral cortex of the aging primate. Macaca nemestrina. J Gerontol 1979;34:642–650PubMedGoogle Scholar
  137. 137.
    Jendrach M, Pohl S, Voth M, Kowald A, Hammerstein P, Bereiter-Hahn J. Morpho-dynamic changes of mitochondria during ageing of human endothelial cells. Mech Ageing Dev 2005;126:813–821PubMedGoogle Scholar
  138. 138.
    Xin MG, Zhang J, Block ER, Patel JM. Senescence-enhanced oxidative stress is associated with deficiency of mitochondrial cytochrome c oxidase in vascular endothelial cells. Mech Ageing Dev 2003;124:911–919PubMedGoogle Scholar
  139. 139.
    van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callender M, Erusalimsky JD, Quaschning T, Malinski T, Gygi D, Ullrich V, Luscher TF. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 2000;192:1731–1744PubMedGoogle Scholar
  140. 140.
    Bellin C, de Wiza DH, Wiernsperger NF, Rosen P. Generation of reactive oxygen species by endothelial and smooth muscle cells: influence of hyperglycemia and metformin. Horm Metab Res 2006;38: 732–739Google Scholar
  141. 141.
    Forstermann U. Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal. Biol Chem 2006;387:1521–1533PubMedGoogle Scholar
  142. 142.
    Topal G, Brunet A, Millanvoye E, Boucher JL, Rendu F, Devynck MA, David-Dufilho M. Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. Free Radic Biol Med 2004;36:1532–1541PubMedGoogle Scholar
  143. 143.
    Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 2006;113:1708–1714PubMedGoogle Scholar
  144. 144.
    Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Inves 1993;91:2546–2551Google Scholar
  145. 145.
    Newaz MA, Yousefipour Z, Oyekan A. Oxidative stress-associated vascular aging is xanthine oxidase-dependent but not NAD(P)H oxidase-dependent. J Cardiovasc Pharmacol 2006;48:88–94PubMedGoogle Scholar
  146. 146.
    Eskurza I, Kahn ZD, Seals DR. Xanthine oxidase does not contribute to impaired peripheral conduit artery endothelium-dependent dilatation with ageing. J Physiol 2006;571:661–668PubMedGoogle Scholar
  147. 147.
    Cardillo C, Kilcoyne CM, Cannon RO 3rd, Quyyumi AA, Panza JA. Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension 1997;30:57–63PubMedGoogle Scholar
  148. 148.
    O’Driscoll JG, Green DJ, Rankin JM, Taylor RR. Nitric oxide-dependent endothelial function is unaffected by allopurinol in hypercholesterolaemic subjects. Clin Exp Pharmacol Physiol 1999;26:779–783PubMedGoogle Scholar
  149. 149.
    Li JM, Shah AM. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 2004;287:R1014–R1030PubMedGoogle Scholar
  150. 150.
    Oudot A, Martin C, Busseuil D, Vergely C, Demaison L, Rochette L. NADPH oxidases are in part responsible for increased cardiovascular superoxide production during aging. Free Radic Biol Med 2006;40:2214–2222PubMedGoogle Scholar
  151. 151.
    Goto K, Fujii K, Onaka U, Abe I, Fujishima M. Angiotensin-converting enzyme inhibitor prevents age-related endothelial dysfunction. Hypertension 2000;36:581–587PubMedGoogle Scholar
  152. 152.
    Mazza F, Goodman A, Lombardo G, Vanella A, Abraham NG. Heme oxygenase-1 gene expression attenuates angiotensin II-mediated DNA damage in endothelial cells. Exp Biol Med (Maywood) 2003;228:576–583Google Scholar
  153. 153.
    Cai H, Griendling KK, Harrison DG. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 2003;24:471–478PubMedGoogle Scholar
  154. 154.
    Ago T, Kitazono T, Ooboshi H, Iyama T, Han YH, Takada J, Wakisaka M, Ibayashi S, Utsumi H, Iida M. Nox4 as the major catalytic component of an endothelial NAD(P)H oxidase. Circulation 2004;109:227–233PubMedGoogle Scholar
  155. 155.
    Guzik TJ, Sadowski J, Kapelak B, Jopek A, Rudzinski P, Pillai R, Korbut R, Channon KM. Systemic regulation of vascular NAD(P)H oxidase activity and nox isoform expression in human arteries and veins. Arterioscler Thromb Vasc Biol 2004;24:1614–1620PubMedGoogle Scholar
  156. 156.
    Bayraktutan U, Blayney L, Shah AM. Molecular characterization and localization of the NAD(P)H oxidase components gp91-phox and p22-phox in endothelial cells. Arterioscler Thromb Vasc Biol 2000;20: 1903–1911PubMedGoogle Scholar
  157. 157.
    Li JM, Shah AM. Intracellular localization and preassembly of the NADPH oxidase complex in cultured endothelial cells. J Biol Chem 2002;277:19952–19960PubMedGoogle Scholar
  158. 158.
    Bachschmid M, van der Loo B, Schuler K, Labugger R, Thurau S, Eto M, Kilo J, Holz R, Luscher TF, Ullrich V. Oxidative stress-associated vascular aging is independent of the protein kinase C/NAD(P)H oxidase pathway. Arch Gerontol Geriatr 2004;38:181–90PubMedGoogle Scholar
  159. 159.
    Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest 1996;97:1916–1923PubMedGoogle Scholar
  160. 160.
    Li H, Witte K, August M, Brausch I, Gödtel-Armbrust U, Habermeier A, Closs EI, Oelze M, Münzel T, Förstermann U. Reversal of eNOS uncoupling and upregulation of eNOS expression lowers blood pressure in hypertensive rats. J Am Coll Cardiol 2006;47:2536–2544PubMedGoogle Scholar
  161. 161.
    Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, Bohm M, Meinertz T, Munzel T. Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation 1999;99:2027–2033PubMedGoogle Scholar
  162. 162.
    Sorescu D, Weiss D, Lassegue B, Clempus RE, Szocs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD, Taylor WR, Griendling KK. Superoxide production and expression of Nox family proteins in human atherosclerosis. Circulation 2002;105:1429–1435PubMedGoogle Scholar
  163. 163.
    Vergnani L, Hatrik S, Ricci F, Passaro A, Manzoli N, Zuliani G, Brovkovych V, Fellin R, Malinski T. Effect of native and oxidized low-density lipoprotein on endothelial nitric oxide and superoxide production: key role of L-arginine availability. Circulation 2000;101:1261–1266PubMedGoogle Scholar
  164. 164.
    Nickenig G, Baumer AT, Temur Y, Kebben D, Jockenhovel F, Bohm M. Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men. Circulation 1999;100:2131–2134PubMedGoogle Scholar
  165. 165.
    Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 2000;86:494–501PubMedGoogle Scholar
  166. 166.
    Dernbach E, Urbich C, Brandes RP, Hofmann WK, Zeiher AM, Dimmeler S. Antioxidative stress-associated genes in circulating progenitor cells: evidence for enhanced resistance against oxidative stress. Blood 2004;104:3591–3597PubMedGoogle Scholar
  167. 167.
    Imanishi T, Hano T, Nishio I. Angiotensin II accelerates endothelial progenitor cell senescence through induction of oxidative stress. J Hypertens 2005;23:97–104PubMedGoogle Scholar
  168. 168.
    Imanishi T, Hano T, Nishio I. Estrogen reduces angiotensin II-induced acceleration of senescence in endothelial progenitor cells. Hypertens Res 2005;28:263–271PubMedGoogle Scholar
  169. 169.
    Kuki S, Imanishi T, Kobayashi K, Matsuo Y, Obana M, Akasaka T. Hyperglycemia accelerated endothelial progenitor cell senescence via the activation of p38 mitogen-activated protein kinase. Circ J 2006;70:1076–1081PubMedGoogle Scholar
  170. 170.
    Callaghan MJ, Ceradini DJ, Gurtner GC. Hyperglycemia-induced reactive oxygen species and impaired endothelial progenitor cell function. Antioxid Redox Signal 2005;7:1476–1482PubMedGoogle Scholar
  171. 171.
    Kobayashi K, Imanishi T, Akasaka T. Endothelial progenitor cell differentiation and senescence in an angiotensin II-infusion rat model. Hypertens Res 2006;29:449–455PubMedGoogle Scholar
  172. 172.
    Zhang W, Zhang G, Jin H, Hu R. Characteristics of bone marrow-derived endothelial progenitor cells in aged mice. Biochem Biophys Res Commun 2006;348:1018–1023PubMedGoogle Scholar
  173. 173.
    Orlandi A, Bochaton-Piallat ML, Gabbiani G, Spagnoli LG. Aging, smooth muscle cells and vascular pathobiology: implications for atherosclerosis. Atherosclerosis 2006;188:221–230PubMedGoogle Scholar
  174. 174.
    Moon SK, Cha BY, Lee YC, Nam KS, Runge MS, Patterson C, Kim CH. Age-related changes in matrix metalloproteinase-9 regulation in cultured mouse aortic smooth muscle cells. Exp Gerontol 2004;39:123–131PubMedGoogle Scholar
  175. 175.
    Li Z, Froehlich J, Galis ZS, Lakatta EG. Increased expression of matrix metalloproteinase-2 in the thickened intima of aged rats. Hypertension 1999;33:116–123PubMedGoogle Scholar
  176. 176.
    Moon SK, Thompson LJ, Madamanchi N, Ballinger S, Papaconstantinou J, Horaist C, Runge MS, Patterson C. Aging, oxidative responses, and proliferative capacity in cultured mouse aortic smooth muscle cells. Am J Physiol Heart Circ Physiol 2001;280:H2779–H2788PubMedGoogle Scholar
  177. 177.
    McCaffrey TA, Nicholson AC, Szabo PE, Weksler ME, Weksler BB. Aging and arteriosclerosis. The increased proliferation of arterial smooth muscle cells isolated from old rats is associated with increased platelet-derived growth factor-like activity. J Exp Med 1988;167:163–174Google Scholar
  178. 178.
    Li Z, Cheng H, Lederer WJ, Froehlich J, Lakatta EG. Enhanced proliferation and migration and altered cytoskeletal proteins in early passage smooth muscle cells from young and old rat aortic explants. Exp Mol Pathol 1997;64:1–11PubMedGoogle Scholar
  179. 179.
    Vazquez-Padron RI, Lasko D, Li S, Louis L, Pestana IA, Pang M, Liotta C, Fornoni A, Aitouche A, Pham SM. Aging exacerbates neointimal formation, and increases proliferation and reduces susceptibility to apoptosis of vascular smooth muscle cells in mice. J Vasc Surg 2004;40:1199–1207PubMedGoogle Scholar
  180. 180.
    Ruiz-Torres A, Gimeno A, Melon J, Mendez L, Munoz FJ, Macia M. Age-related loss of proliferative activity of human vascular smooth muscle cells in culture. Mech Ageing Dev 1999;110:49–55PubMedGoogle Scholar
  181. 181.
    Ruiz-Torres A, Lozano R, Melon J, Carraro R. Age-dependent decline of in vitro migration (basal and stimulated by IGF-1 or insulin) of human vascular smooth muscle cells. J Gerontol A Biol Sci Med Sci 2003;58:B1074–B1077PubMedGoogle Scholar
  182. 182.
    Vigetti D, Moretto P, Viola M, Genasetti A, Rizzi M, Karousou E, Pallotti F, De Luca G, Passi A. Matrix metalloproteinase 2 and tissue inhibitors of metalloproteinases regulate human aortic smooth muscle cell migration during in vitro aging. FASEB J 2006;20:1118–1130PubMedGoogle Scholar
  183. 183.
    Fenton M, Barker S, Kurz DJ, Erusalimsky JD. Cellular senescence after single and repeated balloon catheter denudations of rabbit carotid arteries. Arterioscler Thromb Vasc Biol 2001;21:220–226PubMedGoogle Scholar
  184. 184.
    Marin J. Age-related changes in vascular responses: a review. Mech Ageing Dev 1995;79:71–114PubMedGoogle Scholar
  185. 185.
    Crass MF 3rd, Borst SE, Scarpace PJ. Beta-adrenergic responsiveness in cultured aorta smooth muscle cells. Effects of subculture and aging. Biochem Pharmacol 1992;43:1811–1815PubMedGoogle Scholar
  186. 186.
    Robert L, Robert AM, Jacotot B. Elastin-elastase-atherosclerosis revisited. Atherosclerosis 1998;140:281–295PubMedGoogle Scholar
  187. 187.
    Spinetti G, Wang M, Monticone R, Zhang J, Zhao D, Lakatta EG. Rat aortic MCP-1 and its receptor CCR2 increase with age and alter vascular smooth muscle cell function. Arterioscler Thromb Vasc Biol 2004;24:1397–1402PubMedGoogle Scholar
  188. 188.
    Yamamoto M, Yamamoto K. Growth regulation in primary culture of rabbit arterial smooth muscle cells by platelet-derived growth factor, insulin-like growth factor-I, and epidermal growth factor. Exp Cell Res 1994;212:62–68PubMedGoogle Scholar
  189. 189.
    Fukai N, Aoyagi M, Yamamoto M, Sakamoto H, Ogami K, Matsushima Y, Yamamoto K. Human arterial smooth muscle cell strains derived from patients with moyamoya disease: changes in biological characteristics and proliferative response during cellular aging in vitro. Mech Ageing Dev 1994;75:21–33PubMedGoogle Scholar
  190. 190.
    Aoyagi M, Fukai N, Ogami K, Yamamoto M, Yamamoto K. Kinetics of 125I-PDGF binding and down-regulation of PDGF receptor in human arterial smooth muscle cell strains during cellular senescence in vitro. J Cell Physiol 1995;164:376–384PubMedGoogle Scholar
  191. 191.
    Clarke M, Bennett M. Defining the role of vascular smooth muscle cell apoptosis in atherosclerosis. Cell Cycle 2006;5:2329–2331PubMedGoogle Scholar
  192. 192.
    Gorenne I, Kavurma M, Scott S, Bennett M. Vascular smooth muscle cell senescence in atherosclerosis. Cardiovasc Res 2006;72:9–17PubMedGoogle Scholar
  193. 193.
    Bennett MR, Macdonald K, Chan SW, Boyle JJ, Weissberg PL. Cooperative interactions between RB and p53 regulate cell proliferation, cell senescence, and apoptosis in human vascular smooth muscle cells from atherosclerotic plaques. Circ Res 1998;82:704–712PubMedGoogle Scholar
  194. 194.
    Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P, Ritchie A, Goddard M, Bennett M. Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Circ Res 2006;99:156–164PubMedGoogle Scholar
  195. 195.
    Kunieda T, Minamino T, Nishi J, Tateno K, Oyama T, Katsuno T, Miyauchi H, Orimo M, Okada S, Takamura M, Nagai T, Kaneko S, Komuro I. Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation 2006;114: 953–960PubMedGoogle Scholar
  196. 196.
    Minamino T, Yoshida T, Tateno K, Miyauchi H, Zou Y, Toko H, Komuro I. Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis. Circulation 2003;108:2264–2269PubMedGoogle Scholar
  197. 197.
    Iyemere VP, Proudfoot D, Weissberg PL, Shanahan CM. Vascular smooth muscle cell phenotypic plasticity and the regulation of vascular calcification. J Intern Med 2006;260:192–210PubMedGoogle Scholar
  198. 198.
    Giachelli CM, Speer MY, Li X, Rajachar RM, Yang H. Regulation of vascular calcification: roles of phosphate and osteopontin. Circ Res 2005;96:717–722PubMedGoogle Scholar
  199. 199.
    Jacob T, Ascher E, Hingorani A, Gunduz Y, Kallakuri S. Initial steps in the unifying theory of the pathogenesis of artery aneurysms. J Surg Res 2001;101:37–43PubMedGoogle Scholar
  200. 200.
    Liao S, Curci JA, Kelley BJ, Sicard GA, Thompson RW. Accelerated replicative senescence of medial smooth muscle cells derived from abdominal aortic aneurysms compared to the adjacent inferior mesenteric artery. J Surg Res 2000;92:85–95PubMedGoogle Scholar
  201. 201.
    Gorenne I, Kavurma M, Scott S, Bennett M. Vascular smooth muscle cell senescence in atherosclerosis. Cardiovasc Res 2006;72:9–17PubMedGoogle Scholar
  202. 202.
    Bochaton-Piallat ML, Gabbiani F, Ropraz P, Gabbiani G. Age influences the replicative activity and the differentiation features of cultured rat aortic smooth muscle cell populations and clones. Arterioscler Thromb 1993;13:1449–1455PubMedGoogle Scholar
  203. 203.
    Jones MR, Ravid K. Vascular smooth muscle polyploidization as a biomarker for aging and its impact on differential gene expression. J Biol Chem 2004;279:5306–5313PubMedGoogle Scholar
  204. 204.
    Illi B, Gaetano C, Capogrossi MC. How senescent vascular cells lose their clock age-dependent impairment of circadian rhythmicity in smooth muscle cells. Circ Res 2006;98:450–452PubMedGoogle Scholar
  205. 205.
    Kunieda T, Minamino T, Katsuno T, Tateno K, Nishi J-I, Miyauchi H, Orimo M, Ohada S, Komuro I. Cellular senescence impairs circadian expression of clock genes in vitro and in vivo. Circ Res 2006;98:532–539PubMedGoogle Scholar
  206. 206.
    Abbate R, Prisco D, Rostagno C, Boddi M, Gensini GF. Age-related changes in the hemostatic system. Int J Clin Lab Res 1993;23:1–3PubMedGoogle Scholar
  207. 207.
    Hashimoto Y, Kobayashi A, Yamazaki N, Sugawara Y, Takada Y, Takada A. Relationship between age and plasma t-PA, PA-inhibitor, and PA activity. Thromb Res 1987;46:625–633PubMedGoogle Scholar
  208. 208.
    Conlan MG, Folsom AR, Finch A, Davis CE, Sorlie P, Wu KK. Correlation of plasma protein C levels with cardiovascular risk factors in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost 1993;70:762–767PubMedGoogle Scholar
  209. 209.
    Conlan MG, Folsom AR, Finch A, Davis CE, Marcucci G, Sorlie P, Wu KK. Antithrombin III: associations with age, race, sex and cardiovascular disease risk factors. Thromb Haemost 1994;72:551–556PubMedGoogle Scholar
  210. 210.
    Yamamoto K, Takeshita K, Kojima T, Takamatsu J, Saito H. Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly. Cardiovasc Res 2005;66:276–285PubMedGoogle Scholar
  211. 211.
    Sweeney JD, Hoernig LA. Age-dependent effect on the level of factor IX. Am J Clin Pathol 1993;99:687–688PubMedGoogle Scholar
  212. 212.
    Kurachi S, Hitomi E, Kurachi K. Age and sex-dependent regulation of the factor IX gene in mice. Thromb Haemost 1996;76:965–969PubMedGoogle Scholar
  213. 213.
    Kurachi S, Deyashiki Y, Takeshita J, Kurachi K. Genetic mechanisms of age regulation of human blood coagulation factor IX. Science 1999;285:739–743PubMedGoogle Scholar
  214. 214.
    Zhang K, Kurachi S, Kurachi K. Genetic mechanisms of age regulation of protein C and blood coagulation. J Biol Chem 2002;277:4532–4540PubMedGoogle Scholar
  215. 215.
    Mari D, Mannucci PM, Coppola R, Bottasso B, Bauer KA, Rosenberg RD. Hypercoagulability in centenarians: the paradox of successful aging. Blood 1995;85:3144–3149PubMedGoogle Scholar
  216. 216.
    Wilkerson WR, Sane DC. Aging and thrombosis. Semin Thromb Hemost 2002;28:555–568PubMedGoogle Scholar
  217. 217.
    Shelton DN, Chang E, Whittier PS, Choi D, Funk WD. Microarray analysis of replicative senescence. Curr Biol 1999;9:939–945PubMedGoogle Scholar
  218. 218.
    Labat-Robert J. Cell-matrix interactions, alterations with aging, involvement in angiogenesis. Pathol Biol (Paris) 1998;46:527–533Google Scholar
  219. 219.
    Reed MJ, Edelberg JM. Impaired angiogenesis in the aged. Sci Aging Knowledge Environ 2004;2004:pe7Google Scholar
  220. 220.
    Edelberg JM, Reed MJ. Aging and angiogenesis. Front Biosci 2003;8:s1199–s1209PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • José Marín-García
    • 1
  • Michael J. Goldenthal
    • 2
  • Gordon W. Moe
    • 3
  1. 1.The Molecular Cardiology and Neuromuscular InstituteHighland Park
  2. 2.The Molecular Cardiology and Neuromuscular InstituteHighland Park
  3. 3.University of TorontoTorontoCanada

Personalised recommendations