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Age-Related Endothelial Dysfunction

Potential Implications for Pharmacotherapy

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Abstract

Aging per se is associated with abnormalities of the vascular wall linked to both structural and functional changes that can take place at the level of the extracellular matrix, the vascular smooth muscle and the endothelium of blood vessels. Endothelial dysfunction is generally defined as a decrease in the capacity of the endothelium to dilate blood vessels in response to physical and chemical stimuli. It is one of the characteristic changes that occur with age, independently of other known cardiovascular risk factors. This may account in part for the increased incidence of cardiovascular events in elderly people that can be reversed by restoring endothelial function. A better understanding of the mechanisms involved and the aetiopathogenesis of this process will help in the search for new therapeutic agents.

Age-dependent alteration of endothelium-dependent relaxation seems to be a widespread phenomenon both in conductance and resistance arteries from several species. In the course of aging, there is an alteration in the equilibrium between relaxing and contracting factors released by the endothelium. Hence, there is a progressive reduction in the participation of nitric oxide and endothelium-derived hyperpolarising factor associated with increased participation of oxygen-derived free radicals and cyclo-oxygenase-derived prostanoids. Also, the endothelin-1 and angiotensin II pathways may play a role in age-related endothelial dysfunction. The use of drugs acting at different levels of these signalling cascades, including antioxidant therapy, lipid-lowering drugs and estrogens, seems to be promising.

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References

  1. Fishman AP. Endothelium: a distributed organ of diverse capabilities. Ann N Y Acad Sci 1982; 401: 1–8

    Article  PubMed  CAS  Google Scholar 

  2. Busse R, Fleming I. Pulsatile stretch and shear stress: physical stimuli determining the production of endothelium-derived relaxing factors. J Vasc Res 1998; 35(2): 73–84

    Article  PubMed  CAS  Google Scholar 

  3. Davis MJ, Hill MA. Signaling mechanisms underlying the vascular myogenic response. Physiol Rev 1999; 79(2): 387–423

    PubMed  CAS  Google Scholar 

  4. Vanhoutte PM. Endothelium and control of vascular function: state of the art lecture. Hypertension 1989; 13 (6 Pt 2): 658–67

    Article  PubMed  CAS  Google Scholar 

  5. Colden-Stanfield M, Schilling WP, Ritchie AK, et al. Bradykinin-induced increases in cytosolic calcium and ionic currents in cultured bovine aortic endothelial cells. Circ Res 1987; 61(5): 632–40

    Article  PubMed  CAS  Google Scholar 

  6. Danthuluri NR, Cybulsky MI, Brock TA. ACh-induced calcium transients in primary cultures of rabbit aortic endothelial cells. Am J Physiol 1988; 255 (6 Pt 2): H1549–53

    PubMed  CAS  Google Scholar 

  7. Yokokawa K, Kohno M, Murakawa K, et al. Effect of endothelin-1 on cytosolic calcium ions in cultured human endothelial cells. J Hypertens 1990; 8(9): 843–9

    Article  PubMed  CAS  Google Scholar 

  8. Shin WS, Sasaki T, Kato M, et al. Autocrine and paracrine effects of endothelium-derived relaxing factor on intracellular Ca2+ of endothelial cells and vascular smooth muscle cells: identification by two-dimensional image analysis in coculture. J Biol Chem 1992; 267(28): 20377–82

    PubMed  CAS  Google Scholar 

  9. Rubanyi GM, Vanhoutte PM. Hypoxia releases a vasoconstrictor substance from the canine vascular endothelium. J Physiol 1985; 364: 45–56

    PubMed  CAS  Google Scholar 

  10. Katusic ZS, Vanhoutte PM. Anoxic contractions in isolated canine cerebral arteries: contribution of endothelium-derived factors, metabolites of arachidonic acid, and calcium entry. J Cardiovasc Pharmacol 1986; 8Suppl. 8: S97–101

    Article  PubMed  Google Scholar 

  11. Harder DR. Pressure-induced myogenic activation of cat cerebral arteries is dependent on intact endothelium. Circ Res 1987; 60(1): 102–7

    Article  PubMed  CAS  Google Scholar 

  12. Katusic ZS, Shepherd JT, Vanhoutte PM. Endothelium-dependent contractions to calcium ionophore A23187, arachidonic acid, and acetylcholine in canine basilar arteries. Stroke 1988; 19(4): 476–9

    Article  PubMed  CAS  Google Scholar 

  13. Shimizu S, Ishii M, Yamamoto T, et al. Bradykinin induces generation of reactive oxygen species in bovine aortic endothelial cells. Res Commun Chem Pathol Pharmacol 1994; 84(3): 301–14

    PubMed  CAS  Google Scholar 

  14. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288(5789): 373–6

    Article  PubMed  CAS  Google Scholar 

  15. Ignarro LJ, Buga GM, Wood KS, et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 1987; 84(24): 9265–9

    Article  PubMed  CAS  Google Scholar 

  16. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327(6122): 524–6

    Article  PubMed  CAS  Google Scholar 

  17. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988; 333(6174): 664–6

    Article  PubMed  CAS  Google Scholar 

  18. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43(2): 109–42

    PubMed  CAS  Google Scholar 

  19. Forstermann U, Closs EI, Pollock JS, et al. Nitric oxide synthase isozymes: characterization, purification, molecular cloning, and functions. Hypertension 1994; 23 (6 Pt 2): 1121–31

    Article  PubMed  CAS  Google Scholar 

  20. Venema RC, Sayegh HS, Arnal JF, et al. Role of the enzyme calmodulin-binding domain in membrane association and phospholipid inhibition of endothelial nitric oxide synthase. J Biol Chem 1995; 270(24): 14705–11

    Article  PubMed  CAS  Google Scholar 

  21. Govers R, Rabelink TJ. Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol 2001; 280(2): F193–206

    PubMed  CAS  Google Scholar 

  22. Harris MB, Ju H, Venema VJ, et al. Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation. J Biol Chem 2001; 276(19): 16587–91

    Article  PubMed  CAS  Google Scholar 

  23. Dimmeler S, Dernbach E, Zeiher AM. Phosphorylation of the endothelial nitric oxide synthase at ser-1177 is required for VEGF-induced endothelial cell migration. FEBS Lett 2000; 477(3): 258–62

    Article  PubMed  CAS  Google Scholar 

  24. Brouet A, Sonveaux P, Dessy C, et al. Hsp90 ensures the transition from the early Ca2+-dependent to the late phosphorylation-dependent activation of the endothelial nitric-oxide synthase in vascular endothelial growth factor-exposed endothelial cells. J Biol Chem 2001; 276(35): 32663–9

    Article  PubMed  CAS  Google Scholar 

  25. Scotland RS, Morales-Ruiz M, Chen Y, et al. Functional reconstitution of endothelial nitric oxide synthase reveals the importance of serine 1179 in endothelium-dependent vasomotion. Circ Res 2002; 90(8): 904–10

    Article  PubMed  CAS  Google Scholar 

  26. Hobbs AJ. Soluble guanylate cyclase: the forgotten sibling. Trends Pharmacol Sci 1997; 18(12): 484–91

    Article  PubMed  CAS  Google Scholar 

  27. Lucas KA, Pitari GM, Kazerounian S, et al. Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 2000; 52(3): 375–414

    PubMed  CAS  Google Scholar 

  28. Bolotina VM, Najibi S, Palacino JJ, et al. Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 1994; 368(6474): 850–3

    Article  PubMed  CAS  Google Scholar 

  29. Terlain B, Jouzeau JY, Gillet P, et al. Inducible cyclooxygenase: new relationships between non-steroidal anti-inflammatory agents and inhibition of synthesis of prostaglandins. Presse Med 1995; 24(10): 491–6

    PubMed  CAS  Google Scholar 

  30. Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 1978; 30(3): 293–331

    PubMed  CAS  Google Scholar 

  31. Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev 1999; 79(4): 1193–226

    PubMed  CAS  Google Scholar 

  32. Mitchell JA, Warner TD. Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy. Br J Pharmacol 1999; 128(6): 1121–32

    Article  PubMed  CAS  Google Scholar 

  33. FitzGerald GA. Cardiovascular pharmacology of nonselective nonsteroidal anti-inflammatory drugs and coxibs: clinical considerations. Am J Cardiol 2002; 89(6A): 26D–32D

    Article  PubMed  CAS  Google Scholar 

  34. Bolton TB, Lang RJ, Takewaki T. Mechanisms of action of noradrenaline and carbachol on smooth muscle of guinea-pig anterior mesenteric artery. J Physiol 1984; 351: 549–72

    PubMed  CAS  Google Scholar 

  35. Feletou M, Vanhoutte PM. Endothelium-dependent hyperpolarization of canine coronary smooth muscle. Br J Pharmacol 1988; 93(3): 515–24

    Article  PubMed  CAS  Google Scholar 

  36. Komori K, Suzuki H. Electrical responses of smooth muscle cells during cholinergic vasodilation in the rabbit saphenous artery. Circ Res 1987; 61(4): 586–93

    Article  PubMed  CAS  Google Scholar 

  37. Taylor SG, Southerton JS, Weston AH, et al. Endothelium-dependent effects of acetylcholine in rat aorta: a comparison with sodium nitroprusside and cromakalim. Br J Pharmacol 1988; 94(3): 853–63

    Article  PubMed  CAS  Google Scholar 

  38. Ohlmann P, Martinez MC, Schneider F, et al. Characterization of endothelium-derived relaxing factors released by bradykinin in human resistance arteries. Br J Pharmacol 1997; 121(4): 657–64

    Article  PubMed  CAS  Google Scholar 

  39. Campbell WB, Harder DR. Endothelium-derived hyperpolarizing factors and vascular cytochrome P450 metabolites of arachidonic acid in the regulation of tone. Circ Res 1999; 84(4): 484–8

    Article  PubMed  CAS  Google Scholar 

  40. Corriu C, Feletou M, Canet E, et al. Endothelium-derived factors and hyperpolarization of the carotid artery of the guinea-pig. Br J Pharmacol 1996; 119(5): 959–64

    Article  PubMed  CAS  Google Scholar 

  41. Randall MD, Alexander SP, Bennett T, et al. An endogenous cannabinoid as an endothelium-derived vasorelaxant. Biochem Biophys Res Commun 1996; 229(1): 114–20

    Article  PubMed  CAS  Google Scholar 

  42. Edwards G, Dora KA, Gardener MJ, et al. K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 1998; 396(6708): 269–72

    Article  PubMed  CAS  Google Scholar 

  43. Bolz SS, Fisslthaler B, Pieperhoff S, et al. Antisense oligonucleotides against cytochrome P450 2C8 attenuate EDHF- mediated Ca (2+) changes and dilation in isolated resistance arteries. FASEB J 2000; 14(2): 255–60

    PubMed  CAS  Google Scholar 

  44. Matoba T, Shimokawa H, Nakashima M, et al. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J Clin Invest 2000; 106(12): 1521–30

    Article  PubMed  CAS  Google Scholar 

  45. Dora KA, Garland CJ. Properties of smooth muscle hyperpolarization and relaxation to K+ in the rat isolated mesenteric artery. Am J Physiol Heart Circ Physiol 2001; 280(6): H2424–9

    PubMed  CAS  Google Scholar 

  46. Busse R, Edwards G, Feletou M, et al. EDHF: bringing the concepts together. Trends Pharmacol Sci 2002; 23(8): 374–80

    Article  PubMed  CAS  Google Scholar 

  47. Shimokawa H, Yasutake H, Fujii K, et al. The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation. J Cardiovasc Pharmacol 1996; 28(5): 703–11

    Article  PubMed  CAS  Google Scholar 

  48. Urakami-Harasawa L, Shimokawa H, Nakashima M, et al. Importance of endothelium-derived hyperpolarizing factor in human arteries. J Clin Invest 1997; 100(11): 2793–9

    Article  PubMed  CAS  Google Scholar 

  49. Kato T, Iwama Y, Okumura K, et al. Prostaglandin H2 may be the endothelium-derived contracting factor released by acetylcholine in the aorta of the rat. Hypertension 1990; 15(5): 475–81

    Article  PubMed  CAS  Google Scholar 

  50. Lin L, Nasjletti A. Prostanoid-mediated vascular contraction in normotensive and hypertensive rats. Eur J Pharmacol 1992; 220(1): 49–53

    Article  PubMed  CAS  Google Scholar 

  51. Tesfamariam B. Selective impairment of endothelium-dependent relaxations by prostaglandin endoperoxide. J Hypertens 1994; 12(1): 41–7

    Article  PubMed  CAS  Google Scholar 

  52. Zalba G, Beaumont FJ, San Jose G, et al. Vascular NADH/ NADPH oxidase is involved in enhanced superoxide production in spontaneously hypertensive rats. Hypertension 2000; 35(5): 1055–61

    Article  PubMed  CAS  Google Scholar 

  53. Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol 1986; 250 (5 Pt 2): H822–7

    PubMed  CAS  Google Scholar 

  54. Jin N, Packer CS, Rhoades RA. Reactive oxygen-mediated contraction in pulmonary arterial smooth muscle: cellular mechanisms. Can J Physiol Pharmacol 1991; 69(3): 383–8

    Article  PubMed  CAS  Google Scholar 

  55. Suzuki YJ, Ford GD. Superoxide stimulates IP3-induced Ca2+ release from vascular smooth muscle sarcoplasmic reticulum. Am J Physiol 1992; 262 (1 Pt 2): H114–6

    PubMed  CAS  Google Scholar 

  56. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332(6163): 411–5

    Article  PubMed  CAS  Google Scholar 

  57. Goto K, Hama H, Kasuya Y. Molecular pharmacology and pathophysiological significance of endothelin. Jpn J Pharmacol 1996; 72(4): 261–90

    Article  PubMed  CAS  Google Scholar 

  58. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000; 52(1): 11–34

    PubMed  CAS  Google Scholar 

  59. Berry C, Touyz R, Dominiczak AF, et al. Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide. Am J Physiol Heart Circ Physiol 2001; 281(6): H2337–65

    PubMed  CAS  Google Scholar 

  60. Enseleit F, Hurlimann D, Luscher TF. Vascular protective effects of angiotensin converting enzyme inhibitors and their relation to clinical events. J Cardiovasc Pharmacol 2001; 37Suppl. 1: S21–30

    Article  PubMed  CAS  Google Scholar 

  61. Rossi GP, Seccia TM, Nussdorfer GG. Reciprocal regulation of endothelin-1 and nitric oxide: relevance in the physiology and pathology of the cardiovascular system. Int Rev Cytol 2001; 209: 241–72

    Article  PubMed  CAS  Google Scholar 

  62. Masaki T. Possible role of endothelin in endothelial regulation of vascular tone. Annu Rev Pharmacol Toxicol 1995; 35: 235–55

    Article  PubMed  CAS  Google Scholar 

  63. Pries AR, Secomb TW, Gaehtgens P. The endothelial surface layer. Pflugers Arch 2000; 440(5): 653–66

    Article  PubMed  CAS  Google Scholar 

  64. Simionescu M, Gafencu A, Antohe F. Transcytosis of plasma macromolecules in endothelial cells: a cell biological survey. Microsc Res Tech 2002; 57(5): 269–88

    Article  PubMed  CAS  Google Scholar 

  65. Ogawa K, Imai M, Ogawa T, et al. Caveolar and intercellular channels provide major transport pathways of macromolecules across vascular endothelial cells. Anat Rec 2001; 264(1): 32–42

    Article  PubMed  CAS  Google Scholar 

  66. Minshall RD, Tiruppathi C, Vogel SM, et al. Vesicle formation and trafficking in endothelial cells and regulation of endothelial barrier function. Histochem Cell Biol 2002; 117(2): 105–12

    Article  PubMed  CAS  Google Scholar 

  67. Alexander JS, Elrod JW. Extracellular matrix, junctional integrity and matrix metalloproteinase interactions in endothelial permeability regulation. J Anat 2002; 200(6): 561–74

    Article  PubMed  CAS  Google Scholar 

  68. Bogatcheva NV, Garcia JG, Verin AD. Molecular mechanisms of thrombin-induced endothelial cell permeability. Biochemistry (Mosc) 2002; 67(1): 75–84

    Article  CAS  Google Scholar 

  69. Patel KD, Cuvelier SL, Wiehler S. Selectins: critical mediators of leukocyte recruitment. Semin Immunol 2002; 14(2): 73–81

    Article  PubMed  CAS  Google Scholar 

  70. Toborek M, Kaiser S. Endothelial cell functions: relationship to atherogenesis. Basic Res Cardiol 1999; 94(5): 295–314

    Article  PubMed  CAS  Google Scholar 

  71. Pearson JD. Endothelial cell function and thrombosis. Baillieres Best Pract Res Clin Haematol 1999; 12(3): 329–41

    Article  PubMed  CAS  Google Scholar 

  72. Becker BF, Heindl B, Kupatt C, et al. Endothelial function and hemostasis. Z Kardiol 2000; 89(3): 160–7

    PubMed  CAS  Google Scholar 

  73. Preissner KT, Nawroth PP, Kanse SM. Vascular protease receptors: integrating haemostasis and endothelial cell functions. J Pathol 2000; 190(3): 360–72

    Article  PubMed  CAS  Google Scholar 

  74. Wei JY. Age and the cardiovascular system. N Engl J Med 1992; 327(24): 1735–9

    Article  PubMed  CAS  Google Scholar 

  75. Folkow B, Svanborg A. Physiology of cardiovascular aging. Physiol Rev 1993; 73(4): 725–64

    PubMed  CAS  Google Scholar 

  76. Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 1993; 73(2): 413–67

    PubMed  CAS  Google Scholar 

  77. Gaballa MA, Jacob CT, Raya TE, et al. Large artery remodeling during aging: biaxial passive and active stiffness. Hypertension 1998; 32(3): 437–43

    Article  PubMed  CAS  Google Scholar 

  78. Hongo K, Nakagomi T, Kassell NF, et al. Effects of aging and hypertension on endothelium-dependent vascular relaxation in rat carotid artery. Stroke 1988; 19(7): 892–7

    Article  PubMed  CAS  Google Scholar 

  79. Koga T, Takata Y, Kobayashi K, et al. Ageing suppresses endothelium-dependent relaxation and generates contraction mediated by the muscarinic receptors in vascular smooth muscle of normotensive Wistar-Kyoto and spontaneously hypertensive rats. J Hypertens Suppl 1988; 6(4): S243–5

    PubMed  CAS  Google Scholar 

  80. Kung CF, Luscher TF. Different mechanisms of endothelial dysfunction with aging and hypertension in rat aorta. Hypertension 1995; 25(2): 194–200

    Article  PubMed  CAS  Google Scholar 

  81. Matz RL, de Sotomayor MA, Schott C, et al. Vascular bed heterogeneity in age-related endothelial dysfunction with respect to NO and eicosanoids. Br J Pharmacol 2000; 131(2): 303–11

    Article  PubMed  CAS  Google Scholar 

  82. Muller-Delp J, Spier SA, Ramsey MW, et al. Effects of aging on vasoconstrictor and mechanical properties of rat skeletal muscle arterioles. Am J Physiol Heart Circ Physiol 2002; 282(5): H1843–54

    PubMed  CAS  Google Scholar 

  83. Shimizu I, Toda N. Alterations with age of the response to vasodilator agents in isolated mesenteric arteries of the beagle. Br J Pharmacol 1986; 89(4): 769–78

    Article  PubMed  CAS  Google Scholar 

  84. Haidet GC, Wennberg PW, Rector TS. Aging and vasoreactivity: in vivo responses in the beagle hindlimb. Am J Physiol 1995; 268 (1 Pt 2): H92–9

    PubMed  CAS  Google Scholar 

  85. Egashira K, Inou T, Hirooka Y, et al. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation 1993; 88(1): 77–81

    Article  PubMed  CAS  Google Scholar 

  86. Celermajer DS, Sorensen KE, Spiegelhalter DJ, et al. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 1994; 24(2): 471–6

    Article  PubMed  CAS  Google Scholar 

  87. Taddei S, Virdis A, Mattei P, et al. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 1995; 91(7): 1981–7

    Article  PubMed  CAS  Google Scholar 

  88. Gerhard M, Roddy MA, Creager SJ, et al. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension 1996; 27(4): 849–53

    Article  PubMed  CAS  Google Scholar 

  89. Barton M, Cosentino F, Brandes RP, et al. Anatomic heterogeneity of vascular aging: role of nitric oxide and endothelin. Hypertension 1997; 30(4): 817–24

    Article  PubMed  CAS  Google Scholar 

  90. Moritoki H, Hosoki E, Ishida Y. Age-related decrease in endothelium-dependent dilator response to histamine in rat mesenteric artery. Eur J Pharmacol 1986; 126(1–2): 61–7

    Article  PubMed  CAS  Google Scholar 

  91. Mayhan WG, Faraci FM, Baumbach GL, et al. Effects of aging on responses of cerebral arterioles. Am J Physiol 1990; 258 (4 Pt 2): H1138–43

    PubMed  CAS  Google Scholar 

  92. Fujii K, Ohmori S, Tominaga M, et al. Age-related changes in endothelium-dependent hyperpolarization in the rat mesenteric artery. Am J Physiol 1993; 265 (2 Pt 2): H509–16

    PubMed  CAS  Google Scholar 

  93. Atkinson J, Tatchum-Talom R, Capdeville-Atkinson C. Reduction of endothelial function with age in the mesenteric arterial bed of the normotensive rat. Br J Pharmacol 1994; 111(4): 1184–8

    Article  PubMed  CAS  Google Scholar 

  94. Hatake K, Kakishita E, Wakabayashi I, et al. Effect of aging on endothelium-dependent vascular relaxation of isolated human basilar artery to thrombin and bradykinin. Stroke 1990; 21(7): 1039–43

    Article  PubMed  CAS  Google Scholar 

  95. Hajdu MA, McElmurry RT, Heistad DD, et al. Effects of aging on cerebral vascular responses to serotonin in rats. Am J Physiol 1993; 264 (6 Pt 2): H2136–40

    PubMed  CAS  Google Scholar 

  96. Sarabi M, Millgard J, Lind L. Effects of age, gender and metabolic factors on endothelium-dependent vasodilation: a population-based study. J Intern Med 1999; 246(3): 265–74

    Article  PubMed  CAS  Google Scholar 

  97. Taddei S, Virdis A, Ghiadoni L, et al. Menopause is associated with endothelial dysfunction in women. Hypertension 1996; 28(4): 576–82

    Article  PubMed  CAS  Google Scholar 

  98. Woo KS, McCrohon JA, Chook P, et al. Chinese adults are less susceptible than whites to age-related endothelial dysfunction. J Am Coll Cardiol 1997; 30(1): 113–8

    Article  PubMed  CAS  Google Scholar 

  99. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995; 333(5): 276–82

    Article  PubMed  CAS  Google Scholar 

  100. Woo J, Woo KS, Leung SS, et al. The Mediterranean score of dietary habits in Chinese populations in four different geographical areas. Eur J Clin Nutr 2001; 55(3): 215–20

    Article  PubMed  CAS  Google Scholar 

  101. Woo KS, Chook P, Raitakari OT, et al. Westernization of Chinese adults and increased subclinical atherosclerosis. Arterioscler Thromb Vasc Biol 1999; 19(10): 2487–93

    Article  PubMed  CAS  Google Scholar 

  102. Taddei S, Galetta F, Virdis A, et al. Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes. Circulation 2000; 101(25): 2896–901

    Article  PubMed  CAS  Google Scholar 

  103. Jensen-Urstad K, Johansson J. Gender difference in age-related changes in vascular function. J Intern Med 2001; 250(1): 29–36

    Article  PubMed  CAS  Google Scholar 

  104. Andrawis N, Jones DS, Abernethy DR. Aging is associated with endothelial dysfunction in the human forearm vasculature. J Am Geriatr Soc 2000; 48(2): 193–8

    PubMed  CAS  Google Scholar 

  105. Taddei S, Virdis A, Ghiadoni L, et al. Age-related reduction of NO availability and oxidative stress in humans. Hypertension 2001; 38(2): 274–9

    Article  PubMed  CAS  Google Scholar 

  106. Chinellato A, Pandolfo L, Ragazzi E, et al. Effect of age on rabbit aortic responses to relaxant endothelium- dependent and endothelium-independent agents. Blood Vessels 1991; 28(5): 358–65

    PubMed  CAS  Google Scholar 

  107. Algotsson A, Nordberg A, Winblad B. Influence of age and gender on skin vessel reactivity to endothelium-dependent and endothelium-independent vasodilators tested with iontophoresis and a laser Doppler perfusion imager. J Gerontol A Biol Sci Med Sci 1995; 50(2): M121–7

    Article  PubMed  CAS  Google Scholar 

  108. Singh N, Prasad S, Singer DR, et al. Ageing is associated with impairment of nitric oxide and prostanoid dilator pathways in the human forearm. Clin Sci (Lond) 2002; 102(5): 595–600

    Article  CAS  Google Scholar 

  109. Csiszar A, Ungvari Z, Edwards JG, et al. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res 2002; 90(11): 1159–66

    Article  PubMed  CAS  Google Scholar 

  110. Xiong Y, Yuan LW, Deng HW, et al. Elevated serum endogenous inhibitor of nitric oxide synthase and endothelial dysfunction in aged rats. Clin Exp Pharmacol Physiol 2001; 28(10): 842–7

    Article  PubMed  CAS  Google Scholar 

  111. Taddei S, Virdis A, Mattei P, et al. Hypertension causes premature aging of endothelial function in humans. Hypertension 1997; 29(3): 736–43

    Article  PubMed  CAS  Google Scholar 

  112. Chauhan A, More RS, Mullins PA, et al. Aging-associated endothelial dysfunction in humans is reversed by L- arginine. J Am Coll Cardiol 1996; 28(7): 1796–804

    Article  PubMed  CAS  Google Scholar 

  113. Drexler H, Zeiher AM, Meinzer K, et al. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 1991; 338 (8782–8783): 1546–50

    Article  PubMed  CAS  Google Scholar 

  114. Creager MA, Gallagher SJ, Girerd XJ, et al. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 1992; 90(4): 1248–53

    Article  PubMed  CAS  Google Scholar 

  115. Stoclet JC, Muller B, Gyorgy K, et al. The inducible nitric oxide synthase in vascular and cardiac tissue. Eur J Pharmacol 1999; 375(1–3): 139–55

    Article  PubMed  CAS  Google Scholar 

  116. Zhang C, Hein TW, Wang W, et al. Constitutive expression of arginase in microvascular endothelial cells counteracts nitric oxide-mediated vasodilatory function. FASEB J 2001; 15(7): 1264–6

    PubMed  CAS  Google Scholar 

  117. Vallance P, Leone A, Calver A, et al. Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis. J Cardiovasc Pharmacol 1992; 20Suppl. 12: S60–2

    Article  PubMed  CAS  Google Scholar 

  118. Boger RH, Bode-Boger SM, Szuba A, et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998; 98(18): 1842–7

    Article  PubMed  CAS  Google Scholar 

  119. Usui M, Matsuoka H, Miyazaki H, et al. Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. Life Sci 1998; 62(26): 2425–30

    Article  PubMed  CAS  Google Scholar 

  120. Surdacki A, Nowicki M, Sandmann J, et al. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol 1999; 33(4): 652–8

    Article  PubMed  CAS  Google Scholar 

  121. Fleming I, Busse R. Signal transduction of eNOS activation. Cardiovasc Res 1999; 43(3): 532–41

    Article  PubMed  CAS  Google Scholar 

  122. Cosentino F, Luscher TF. Tetrahydrobiopterin and endothelial nitric oxide synthase activity. Cardiovasc Res 1999; 43(2): 274–8

    Article  PubMed  CAS  Google Scholar 

  123. Cernadas MR, Sanchez de Miguel L, Garcia-Duran M, et al. Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats. Circ Res 1998; 83(3): 279–86

    Article  PubMed  CAS  Google Scholar 

  124. van der Loo B, Labugger R, Skepper JN, et al. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 2000; 192(12): 1731–44

    Article  PubMed  Google Scholar 

  125. Chou TC, Yen MH, Li CY, et al. Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension 1998; 31(2): 643–8

    Article  PubMed  CAS  Google Scholar 

  126. Stamler JS. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 1994; 78(6): 931–6

    Article  PubMed  CAS  Google Scholar 

  127. Mugge A, Elwell JH, Peterson TE, et al. Release of intact endothelium-derived relaxing factor depends on endothelial superoxide dismutase activity. Am J Physiol 1991; 260 (2 Pt 1): C219–25

    PubMed  CAS  Google Scholar 

  128. Stadtman ER. Protein oxidation and aging. Science 1992; 257(5074): 1220–4

    Article  PubMed  CAS  Google Scholar 

  129. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science 1996; 273(5271): 59–63

    Article  PubMed  CAS  Google Scholar 

  130. Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev 1998; 78(2): 547–81

    PubMed  CAS  Google Scholar 

  131. Perez-Campo R, Lopez-Torres M, Cadenas S, et al. The rate of free radical production as a determinant of the rate of aging: evidence from the comparative approach. J Comp Physiol [B] 1998; 168(3): 149–58

    Article  CAS  Google Scholar 

  132. Vanhoutte PM. Endothelium-derived free radicals: for worse and for better. J Clin Invest 2001; 107(1): 23–5

    Article  PubMed  CAS  Google Scholar 

  133. Rodriguez-Martinez MA, Alonso MJ, Redondo J, et al. Role of lipid peroxidation and the glutathione-dependent antioxidant system in the impairment of endothelium-dependent relaxations with age. Br J Pharmacol 1998; 123(1): 113–21

    Article  PubMed  CAS  Google Scholar 

  134. Varani J, Ward PA. Mechanisms of neutrophil-dependent and neutrophil-independent endothelial cell injury. Biol Signals 1994; 3(1): 1–14

    Article  PubMed  CAS  Google Scholar 

  135. Miller Jr FJ, Gutterman DD, Rios CD, et al. Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis. Circ Res 1998; 82(12): 1298–305

    Article  PubMed  CAS  Google Scholar 

  136. Hamilton CA, Brosnan MJ, McIntyre M, et al. Superoxide excess in hypertension and aging: a common cause of endothelial dysfunction. Hypertension 2001; 37 (2 Part 2): 529–34

    Article  PubMed  CAS  Google Scholar 

  137. Pacher P, Mabley JG, Soriano FG, et al. Endothelial dysfunction in aging animals: the role of poly (ADP-ribose) polymerase activation. Br J Pharmacol 2002; 135(6): 1347–50

    Article  PubMed  CAS  Google Scholar 

  138. Szabo C. Cell death: the role of PARP. Boca Raton (FL): CRC Press, 2000

    Book  Google Scholar 

  139. Virag L, Szabo C. The therapeutic potential of poly (ADP-Ribose) polymerase inhibitors. Pharmacol Rev 2002; 54(3): 375–429

    Article  PubMed  CAS  Google Scholar 

  140. Thiemermann C, Bowes J, Myint FP, et al. Inhibition of the activity of poly (ADP ribose) synthetase reduces ischemiareperfusion injury in the heart and skeletal muscle. Proc Natl Acad Sci U S A 1997; 94(2): 679–83

    Article  PubMed  CAS  Google Scholar 

  141. Liaudet L, Soriano FG, Szabo E, et al. Protection against hemorrhagic shock in mice genetically deficient in poly (ADP-ribose)polymerase. Proc Natl Acad Sci U S A 2000; 97(18): 10203–8

    Article  PubMed  CAS  Google Scholar 

  142. Soriano FG, Pacher P, Mabley J, et al. Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly (ADP-ribose) polymerase. Circ Res 2001; 89(8): 684–91

    Article  PubMed  CAS  Google Scholar 

  143. Pacher P, Mabley JG, Soriano FG, et al. Activation of poly (ADP-ribose) polymerase contributes to the endothelial dysfunction associated with hypertension and aging. Int J Mol Med 2002; 9(6): 659–64

    PubMed  CAS  Google Scholar 

  144. Cooke JP. Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol 2000; 20(9): 2032–7

    Article  PubMed  CAS  Google Scholar 

  145. Nakashima MVP. Decreased endothelium-dependent hyperpolarisation with aging and hypertension. In: PM Vanhoutte, editor. Endothelium-derived hyperpolarising factor. Amsterdam: Harwood Academic, 1996: 227–33

    Google Scholar 

  146. Mantelli L, Amerini S, Ledda F. Roles of nitric oxide and endothelium-derived hyperpolarizing factor in vasorelaxant effect of acetylcholine as influenced by aging and hypertension. J Cardiovasc Pharmacol 1995; 25(4): 595–602

    Article  PubMed  CAS  Google Scholar 

  147. de Sotomayor MA, Andriantsitohaina R. Effect of ageing on the endothelium-dependent vasorelaxation induced by acetylcholine in rat mesenteric arteries. In: PM Vanhoutte, editor. Endothelium-derived hyperpolarization. Amsterdam: Harwood Academic, 1999: 323–32

    Google Scholar 

  148. Matz RL, Schott C, Stoclet JC, et al. Age-related endothelial dysfunction with respect to nitric oxide, endothelium-derived hyperpolarizing factor and cyclooxygenase products. Physiol Res 2000; 49(1): 11–8

    PubMed  CAS  Google Scholar 

  149. Marijic J, Li Q, Song M, et al. Decreased expression of voltage-and Ca (2+)-activated K (+) channels in coronary smooth muscle during aging. Circ Res 2001; 88(2): 210–6

    Article  PubMed  CAS  Google Scholar 

  150. Koga T, Takata Y, Kobayashi K, et al. Age and hypertension promote endothelium-dependent contractions to acetylcholine in the aorta of the rat. Hypertension 1989; 14(5): 542–8

    Article  PubMed  CAS  Google Scholar 

  151. Heymes C, Habib A, Yang D, et al. Cyclo-oxygenase-1 and -2 contribution to endothelial dysfunction in ageing. Br J Pharmacol 2000; 131(4): 804–10

    Article  PubMed  CAS  Google Scholar 

  152. Stewart KG, Zhang Y, Davidge ST. Aging increases PGH-S-2-dependent vasoconstriction in rat mesenteric arteries. Hypertension 2000; 35(6): 1242–7

    Article  PubMed  CAS  Google Scholar 

  153. Davidge ST, Hubel CA, McLaughlin MK. Impairment of vascular function is associated with an age-related increase of lipid peroxidation in rats. Am J Physiol 1996; 271 (6 Pt 2): R1625–31

    PubMed  CAS  Google Scholar 

  154. Ito T, Kato T, Iwama Y, et al. Prostaglandin H2 as an endothelium-derived contracting factor and its interaction with endothelium-derived nitric oxide. J Hypertens 1991; 9(8): 729–36

    Article  PubMed  CAS  Google Scholar 

  155. Auch-Schwelk W, Katusic ZS, Vanhoutte PM. Nitric oxide inactivates endothelium-derived contracting factor in the rat aorta. Hypertension 1992; 19(5): 442–5

    Article  PubMed  CAS  Google Scholar 

  156. Barton M, Lattmann T, d’Uscio LV, et al. Inverse regulation of endothelin-1 and nitric oxide metabolites in tissue with aging: implications for the age-dependent increase of cardiorenal disease. J Cardiovasc Pharmacol 2000; 36 (5 Suppl. 1): S153–6

    PubMed  CAS  Google Scholar 

  157. Goettsch W, Lattmann T, Amann K, et al. Increased expression of endothelin-1 and inducible nitric oxide synthase isoform II in aging arteries in vivo: implications for atherosclerosis. Biochem Biophys Res Commun 2001; 280(3): 908–13

    Article  PubMed  CAS  Google Scholar 

  158. Maeda S, Miyauchi T, Iemitsu M, et al. Effects of exercise training on expression of endothelin-1 mRNA in the aorta of aged rats. Clin Sci (Lond) 2002; 103Suppl. 48: 118S–23S

    CAS  Google Scholar 

  159. Ishihata A, Katano Y, Nakamura M, et al. Differential modulation of nitric oxide and prostacyclin release in senescent rat heart stimulated by angiotensin II. Eur J Pharmacol 1999; 382(1): 19–26

    Article  PubMed  CAS  Google Scholar 

  160. Halcox JP, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002; 106(6): 653–8

    Article  PubMed  Google Scholar 

  161. Lerman A, Burnett Jr JC, Higano ST, et al. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 1998; 97(21): 2123–8

    Article  PubMed  CAS  Google Scholar 

  162. Preli RB, Klein KP, Herrington DM. Vascular effects of dietary L-arginine supplementation. Atherosclerosis 2002; 162(1): 1–15

    Article  PubMed  CAS  Google Scholar 

  163. Katusic ZS. Vascular endothelial dysfunction: does tetrahydrobiopterin play a role? Am J Physiol Heart Circ Physiol 2001; 281(3): H981–6

    PubMed  CAS  Google Scholar 

  164. Munzel T, Sayegh H, Freeman BA, et al. Evidence for enhanced vascular superoxide anion production in nitrate tolerance: a novel mechanism underlying tolerance and cross-tolerance. J Clin Invest 1995; 95(1): 187–94

    Article  PubMed  CAS  Google Scholar 

  165. Heitzer T, Just H, Munzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation 1996; 94(1): 6–9

    Article  PubMed  CAS  Google Scholar 

  166. Ting HH, Timimi FK, Boles KS, et al. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1996; 97(1): 22–8

    Article  PubMed  CAS  Google Scholar 

  167. May JM. How does ascorbic acid prevent endothelial dysfunction? Free Radic Biol Med 2000; 28(9): 1421–9

    Article  PubMed  CAS  Google Scholar 

  168. Carr A, Frei B. The role of natural antioxidants in preserving the biological activity of endothelium-derived nitric oxide. Free Radic Biol Med 2000; 28(12): 1806–14

    Article  PubMed  CAS  Google Scholar 

  169. Simons LA, von Konigsmark M, Simons J, et al. Vitamin E ingestion does not improve arterial endothelial dysfunction in older adults. Atherosclerosis 1999; 143(1): 193–9

    Article  PubMed  CAS  Google Scholar 

  170. Hara T, Kusunoki M, Tsutsumi K, et al. A lipoprotein lipase activator, NO-1886, improves endothelium-dependent relaxation of rat aorta associated with aging. Eur J Pharmacol 1998; 350(1): 75–9

    Article  PubMed  Google Scholar 

  171. Egashira K, Hirooka Y, Kai H, et al. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994; 89(6): 2519–24

    Article  PubMed  CAS  Google Scholar 

  172. Anderson TJ, Meredith IT, Yeung AC, et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995; 332(8): 488–93

    Article  PubMed  CAS  Google Scholar 

  173. Omori H, Nagashima H, Tsurumi Y, et al. Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects. Br J Clin Pharmacol 2002; 54(4): 395–9

    Article  PubMed  CAS  Google Scholar 

  174. Alvarez De Sotomayor M, Herrera MD, Marhuenda E, et al. Characterization of endothelial factors involved in the vasodilatory effect of simvastatin in aorta and small mesenteric artery of the rat. Br J Pharmacol 2000; 131(6): 1179–87

    Article  PubMed  CAS  Google Scholar 

  175. Alvarez de Sotomayor M, Andriantsitohaina R. Simvastatin and Ca (2+) signaling in endothelial cells: involvement of rho protein. Biochem Biophys Res Commun 2001; 280(2): 486–90

    Article  PubMed  CAS  Google Scholar 

  176. Dobrucki LW, Kalinowski L, Dobrucki IT, et al. Statin-stimulated nitric oxide release from endothelium. Med Sci Monit 2001; 7(4): 622–7

    PubMed  CAS  Google Scholar 

  177. Sessa WC. Can modulation of endothelial nitric oxide synthase explain the vasculoprotective actions of statins? Trends Mol Med 2001; 7(5): 189–91

    Article  PubMed  CAS  Google Scholar 

  178. Vecchione C, Brandes RP. Withdrawal of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors elicits oxidative stress and induces endothelial dysfunction in mice. Circ Res 2002; 91(2): 173–9

    Article  PubMed  CAS  Google Scholar 

  179. Gryglewski RJ, Uracz W, Swies J, et al. Comparison of endothelial pleiotropic actions of angiotensin converting enzyme inhibitors and statins. Ann N Y Acad Sci 2001; 947: 229–45

    Article  PubMed  CAS  Google Scholar 

  180. Lawler OA, Miggin SM, Kinsella BT. The effects of the statins lovastatin and cerivastatin on signalling by the prostanoid IP-receptor. Br J Pharmacol 2001; 132(8): 1639–49

    Article  PubMed  CAS  Google Scholar 

  181. Takemoto M, Liao JK. Pleiotropic effects of 3-hydrox-y-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21(11): 1712–9

    Article  PubMed  CAS  Google Scholar 

  182. Fenton II JW, Jeske WP, Catalfamo JL, et al. Statin drugs and dietary isoprenoids downregulate protein prenylation in signal transduction and are antithrombotic and prothrombolytic agents. Biochemistry (Mosc) 2002; 67(1): 85–91

    Article  CAS  Google Scholar 

  183. Goto K. Basic and therapeutic relevance of endothelin-mediated regulation. Biol Pharm Bull 2001; 24(11): 1219–30

    Article  PubMed  CAS  Google Scholar 

  184. Love MP, McMurray JJ. Endothelin receptor antagonists and cardiovascular diseases of aging. Drugs Aging 2001; 18(6): 425–40

    Article  PubMed  CAS  Google Scholar 

  185. Ergul A. Endothelin-1 and endothelin receptor antagonists as potential cardiovascular therapeutic agents. Pharmacotherapy 2002; 22(1): 54–65

    Article  PubMed  CAS  Google Scholar 

  186. Besse S, Tanguy S, Riou B, et al. Coronary and aortic vasoreactivity protection with endothelin receptor antagonist, bosentan, after ischemia and hypoxia in aged rats. Eur J Pharmacol 2001; 432(2–3): 167–75

    Article  PubMed  CAS  Google Scholar 

  187. Linz W, Wiemer G, Gohlke P, et al. Contribution of kinins to the cardiovascular actions of angiotensin- converting enzyme inhibitors. Pharmacol Rev 1995; 47(1): 25–49

    PubMed  CAS  Google Scholar 

  188. Kuga T, Mohri M, Egashira K, et al. Bradykinin-induced vasodilation of human coronary arteries in vivo: role of nitric oxide and angiotensin-converting enzyme. J Am Coll Cardiol 1997; 30(1): 108–12

    Article  PubMed  CAS  Google Scholar 

  189. Usui M, Egashira K, Tomita H, et al. Important role of local angiotensin II activity mediated via type 1 receptor in the pathogenesis of cardiovascular inflammatory changes induced by chronic blockade of nitric oxide synthesis in rats. Circulation 2000; 101(3): 305–10

    Article  PubMed  CAS  Google Scholar 

  190. Goto K, Fujii K, Onaka U, et al. Angiotensin-converting enzyme inhibitor prevents age-related endothelial dysfunction. Hypertension 2000; 36(4): 581–7

    Article  PubMed  CAS  Google Scholar 

  191. Kansui Y, Fujii K, Goto K, et al. Angiotensin II receptor antagonist improves age-related endothelial dysfunction. J Hypertens 2002; 20(3): 439–46

    Article  PubMed  CAS  Google Scholar 

  192. Maeso R, Rodrigo E, Munoz-Garcia R, et al. Factors involved in the effects of losartan on endothelial dysfunction induced by aging in SHR. Kidney Int Suppl 1998; 68: S30–5

    PubMed  CAS  Google Scholar 

  193. Mukai Y, Shimokawa H, Higashi M, et al. Inhibition of reninangiotensin system ameliorates endothelial dysfunction associated with aging in rats. Arterioscler Thromb Vasc Biol 2002; 22(9): 1445–50

    Article  PubMed  CAS  Google Scholar 

  194. Rajagopalan S, Brook R, Mehta RH, et al. Effect of losartan in aging-related endothelial impairment. Am J Cardiol 2002; 89(5): 562–6

    Article  PubMed  CAS  Google Scholar 

  195. Hayashi T, Yamada K, Esaki T, et al. Estrogen increases endothelial nitric oxide by a receptor-mediated system. Biochem Biophys Res Commun 1995; 214(3): 847–55

    Article  PubMed  CAS  Google Scholar 

  196. McNeill AM, Kim N, Duckles SP, et al. Chronic estrogen treatment increases levels of endothelial nitric oxide synthase protein in rat cerebral microvessels. Stroke 1999; 30(10): 2186–90

    Article  PubMed  CAS  Google Scholar 

  197. Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340(23): 1801–11

    Article  PubMed  CAS  Google Scholar 

  198. Yang S, Bae L, Zhang L. Estrogen increases eNOS and NOx release in human coronary artery endothelium. J Cardiovasc Pharmacol 2000; 36(2): 242–7

    Article  PubMed  CAS  Google Scholar 

  199. Arnal JF, Clamens S, Pechet C, et al. Ethinylestradiol does not enhance the expression of nitric oxide synthase in bovine endothelial cells but increases the release of bioactive nitric oxide by inhibiting superoxide anion production. Proc Natl Acad Sci U S A 1996; 93(9): 4108–13

    Article  PubMed  CAS  Google Scholar 

  200. Virdis A, Ghiadoni L, Pinto S, et al. Mechanisms responsible for endothelial dysfunction associated with acute estrogen deprivation in normotensive women. Circulation 2000; 101(19): 2258–63

    Article  PubMed  CAS  Google Scholar 

  201. Mendelsohn ME. Protective effects of estrogen on the cardiovascular system. Am J Cardiol 2002; 89 (12 Suppl.): 12E–7E

    Article  PubMed  CAS  Google Scholar 

  202. Armstrong SJ, Zhang Y, Stewart KG, et al. Estrogen replacement reduces PGHS-2-dependent vasoconstriction in the aged rat. Am J Physiol Heart Circ Physiol 2002; 283(3): H893–8

    PubMed  CAS  Google Scholar 

  203. Arora S, Veves A, Caballaro AE, et al. Estrogen improves endothelial function. J Vasc Surg 1998; 27(6): 1141–6

    Article  PubMed  CAS  Google Scholar 

  204. Herrington DM, Werbel BL, Riley WA, et al. Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease. J Am Coll Cardiol 1999; 33(7): 2030–7

    Article  PubMed  CAS  Google Scholar 

  205. Akhmedkhanov A, Zeleniuch-Jacquotte A, Toniolo P. Role of exogenous and endogenous hormones in endometrial cancer: review of the evidence and research perspectives. Ann N Y Acad Sci 2001; 943: 296–315

    Article  PubMed  CAS  Google Scholar 

  206. Gerhard M, Walsh BW, Tawakol A, et al. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation 1998; 98(12): 1158–63

    Article  PubMed  CAS  Google Scholar 

  207. Sorensen KE, Dorup I, Hermann AP, et al. Combined hormone replacement therapy does not protect women against the age-related decline in endothelium-dependent vasomotor function. Circulation 1998; 97(13): 1234–8

    Article  PubMed  CAS  Google Scholar 

  208. Sarrel PM. The differential effects of oestrogens and progestins on vascular tone. Hum Reprod Update 1999; 5(3): 205–9

    Article  PubMed  CAS  Google Scholar 

  209. Teoh H, Man RY. Progesterone modulates estradiol actions: acute effects at physiological concentrations. Eur J Pharmacol 1999; 378(1): 57–62

    Article  PubMed  CAS  Google Scholar 

  210. Haines CJ, Yim SF, Sanderson JE. The effect of continuous combined hormone replacement therapy on arterial reactivity in postmenopausal women with established angina pectoris. Atherosclerosis 2001; 159(2): 467–70

    Article  PubMed  CAS  Google Scholar 

  211. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). JAMA 2002; 288(1): 49–57

    Article  PubMed  Google Scholar 

  212. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: scientific review. JAMA 2002; 288(7): 872–81

    Article  PubMed  CAS  Google Scholar 

  213. Herrington DM, Espeland MA, Crouse III JR, et al. Estrogen replacement and brachial artery flow-mediated vasodilation in older women. Arterioscler Thromb Vasc Biol 2001; 21(12): 1955–61

    Article  PubMed  CAS  Google Scholar 

  214. Clarkson P, Montgomery HE, Mullen MJ, et al. Exercise training enhances endothelial function in young men. J Am Coll Cardiol 1999; 33(5): 1379–85

    Article  PubMed  CAS  Google Scholar 

  215. Abbott RA, Harkness MA, Davies PS. Correlation of habitual physical activity levels with flow-mediated dilation of the brachial artery in 5–10 year old children. Atherosclerosis 2002; 160(1): 233–9

    Article  PubMed  CAS  Google Scholar 

  216. Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996; 93(2): 210–4

    Article  PubMed  CAS  Google Scholar 

  217. Schmidt A, Pleiner J, Bayerle-Eder M, et al. Regular physical exercise improves endothelial function in heart transplant recipients. Clin Transplant 2002; 16(2): 137–43

    Article  PubMed  Google Scholar 

  218. Hambrecht R, Wolf A, Gielen S, et al. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med 2000; 342(7): 454–60

    Article  PubMed  CAS  Google Scholar 

  219. Lang CC, Chomsky DB, Butler J, et al. Prostaglandin production contributes to exercise-induced vasodilation in heart failure. J Appl Physiol 1997; 83(6): 1933–40

    PubMed  CAS  Google Scholar 

  220. Hambrecht R, Fiehn E, Weigl C, et al. Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation 1998; 98(24): 2709–15

    Article  PubMed  CAS  Google Scholar 

  221. Griffin KL, Laughlin MH, Parker JL. Exercise training improves endothelium-mediated vasorelaxation after chronic coronary occlusion. J Appl Physiol 1999; 87(5): 1948–56

    PubMed  CAS  Google Scholar 

  222. Varin R, Mulder P, Richard V, et al. Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure: role of nitric oxide, prostanoids, and oxidant stress. Circulation 1999; 99(22): 2951–7

    Article  PubMed  CAS  Google Scholar 

  223. Chu TF, Huang TY, Jen CJ, et al. Effects of chronic exercise on calcium signaling in rat vascular endothelium. Am J Physiol Heart Circ Physiol 2000; 279(4): H1441–6

    PubMed  CAS  Google Scholar 

  224. Ennezat PV, Malendowicz SL, Testa M, et al. Physical training in patients with chronic heart failure enhances the expression of genes encoding antioxidative enzymes. J Am Coll Cardiol 2001; 38(1): 194–8

    Article  PubMed  CAS  Google Scholar 

  225. Griffin KL, Woodman CR, Price EM, et al. Endothelium-mediated relaxation of porcine collateral-dependent arterioles is improved by exercise training. Circulation 2001; 104(12): 1393–8

    Article  PubMed  CAS  Google Scholar 

  226. Jen CJ, Chan HP, Chen HI. Chronic exercise improves endothelial calcium signaling and vasodilatation in hypercholesterolemic rabbit femoral artery. Arterioscler Thromb Vasc Biol 2002; 22(7): 1219–24

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to Dr S.M. Kanse for carefully reading the manuscript. The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.

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  1. Biochemisches Institut, Fachbereich Humanmedizin, Justus Liebig Universität, Giessen, Germany

    Rachel L. Matz

  2. Laboratoire de Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, 74 route du Rhin, UMR CNRS 7034, 67401, Illkirch, France

    Ramaroson Andriantsitohaina

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Matz, R.L., Andriantsitohaina, R. Age-Related Endothelial Dysfunction. Drugs Aging 20, 527–550 (2003). https://doi.org/10.2165/00002512-200320070-00005

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