Drugs & Aging

, Volume 20, Issue 7, pp 527–550 | Cite as

Age-Related Endothelial Dysfunction

Potential Implications for Pharmacotherapy
Review Article

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.

Notes

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.

References

  1. 1.
    Fishman AP. Endothelium: a distributed organ of diverse capabilities. Ann N Y Acad Sci 1982; 401: 1–8PubMedCrossRefGoogle Scholar
  2. 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): 73–84PubMedCrossRefGoogle Scholar
  3. 3.
    Davis MJ, Hill MA. Signaling mechanisms underlying the vascular myogenic response. Physiol Rev 1999; 79(2): 387–423PubMedGoogle Scholar
  4. 4.
    Vanhoutte PM. Endothelium and control of vascular function: state of the art lecture. Hypertension 1989; 13 (6 Pt 2): 658–67PubMedCrossRefGoogle Scholar
  5. 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): 632–40PubMedCrossRefGoogle Scholar
  6. 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): H1549–53PubMedGoogle Scholar
  7. 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): 843–9PubMedCrossRefGoogle Scholar
  8. 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): 20377–82PubMedGoogle Scholar
  9. 9.
    Rubanyi GM, Vanhoutte PM. Hypoxia releases a vasoconstrictor substance from the canine vascular endothelium. J Physiol 1985; 364: 45–56PubMedGoogle Scholar
  10. 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: S97–101PubMedCrossRefGoogle Scholar
  11. 11.
    Harder DR. Pressure-induced myogenic activation of cat cerebral arteries is dependent on intact endothelium. Circ Res 1987; 60(1): 102–7PubMedCrossRefGoogle Scholar
  12. 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): 476–9PubMedCrossRefGoogle Scholar
  13. 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): 301–14PubMedGoogle Scholar
  14. 14.
    Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288(5789): 373–6PubMedCrossRefGoogle Scholar
  15. 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): 9265–9PubMedCrossRefGoogle Scholar
  16. 16.
    Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327(6122): 524–6PubMedCrossRefGoogle Scholar
  17. 17.
    Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988; 333(6174): 664–6PubMedCrossRefGoogle Scholar
  18. 18.
    Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43(2): 109–42PubMedGoogle Scholar
  19. 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): 1121–31PubMedCrossRefGoogle Scholar
  20. 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): 14705–11PubMedCrossRefGoogle Scholar
  21. 21.
    Govers R, Rabelink TJ. Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol 2001; 280(2): F193–206PubMedGoogle Scholar
  22. 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): 16587–91PubMedCrossRefGoogle Scholar
  23. 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): 258–62PubMedCrossRefGoogle Scholar
  24. 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): 32663–9PubMedCrossRefGoogle Scholar
  25. 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): 904–10PubMedCrossRefGoogle Scholar
  26. 26.
    Hobbs AJ. Soluble guanylate cyclase: the forgotten sibling. Trends Pharmacol Sci 1997; 18(12): 484–91PubMedCrossRefGoogle Scholar
  27. 27.
    Lucas KA, Pitari GM, Kazerounian S, et al. Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 2000; 52(3): 375–414PubMedGoogle Scholar
  28. 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): 850–3PubMedCrossRefGoogle Scholar
  29. 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): 491–6PubMedGoogle Scholar
  30. 30.
    Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 1978; 30(3): 293–331PubMedGoogle Scholar
  31. 31.
    Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev 1999; 79(4): 1193–226PubMedGoogle Scholar
  32. 32.
    Mitchell JA, Warner TD. Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy. Br J Pharmacol 1999; 128(6): 1121–32PubMedCrossRefGoogle Scholar
  33. 33.
    FitzGerald GA. Cardiovascular pharmacology of nonselective nonsteroidal anti-inflammatory drugs and coxibs: clinical considerations. Am J Cardiol 2002; 89(6A): 26D–32DPubMedCrossRefGoogle Scholar
  34. 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: 549–72PubMedGoogle Scholar
  35. 35.
    Feletou M, Vanhoutte PM. Endothelium-dependent hyperpolarization of canine coronary smooth muscle. Br J Pharmacol 1988; 93(3): 515–24PubMedCrossRefGoogle Scholar
  36. 36.
    Komori K, Suzuki H. Electrical responses of smooth muscle cells during cholinergic vasodilation in the rabbit saphenous artery. Circ Res 1987; 61(4): 586–93PubMedCrossRefGoogle Scholar
  37. 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): 853–63PubMedCrossRefGoogle Scholar
  38. 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): 657–64PubMedCrossRefGoogle Scholar
  39. 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): 484–8PubMedCrossRefGoogle Scholar
  40. 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): 959–64PubMedCrossRefGoogle Scholar
  41. 41.
    Randall MD, Alexander SP, Bennett T, et al. An endogenous cannabinoid as an endothelium-derived vasorelaxant. Biochem Biophys Res Commun 1996; 229(1): 114–20PubMedCrossRefGoogle Scholar
  42. 42.
    Edwards G, Dora KA, Gardener MJ, et al. K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 1998; 396(6708): 269–72PubMedCrossRefGoogle Scholar
  43. 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): 255–60PubMedGoogle Scholar
  44. 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): 1521–30PubMedCrossRefGoogle Scholar
  45. 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): H2424–9PubMedGoogle Scholar
  46. 46.
    Busse R, Edwards G, Feletou M, et al. EDHF: bringing the concepts together. Trends Pharmacol Sci 2002; 23(8): 374–80PubMedCrossRefGoogle Scholar
  47. 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): 703–11PubMedCrossRefGoogle Scholar
  48. 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): 2793–9PubMedCrossRefGoogle Scholar
  49. 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): 475–81PubMedCrossRefGoogle Scholar
  50. 50.
    Lin L, Nasjletti A. Prostanoid-mediated vascular contraction in normotensive and hypertensive rats. Eur J Pharmacol 1992; 220(1): 49–53PubMedCrossRefGoogle Scholar
  51. 51.
    Tesfamariam B. Selective impairment of endothelium-dependent relaxations by prostaglandin endoperoxide. J Hypertens 1994; 12(1): 41–7PubMedCrossRefGoogle Scholar
  52. 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): 1055–61PubMedCrossRefGoogle Scholar
  53. 53.
    Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol 1986; 250 (5 Pt 2): H822–7PubMedGoogle Scholar
  54. 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): 383–8PubMedCrossRefGoogle Scholar
  55. 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): H114–6PubMedGoogle Scholar
  56. 56.
    Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332(6163): 411–5PubMedCrossRefGoogle Scholar
  57. 57.
    Goto K, Hama H, Kasuya Y. Molecular pharmacology and pathophysiological significance of endothelin. Jpn J Pharmacol 1996; 72(4): 261–90PubMedCrossRefGoogle Scholar
  58. 58.
    Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000; 52(1): 11–34PubMedGoogle Scholar
  59. 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): H2337–65PubMedGoogle Scholar
  60. 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: S21–30PubMedCrossRefGoogle Scholar
  61. 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: 241–72PubMedCrossRefGoogle Scholar
  62. 62.
    Masaki T. Possible role of endothelin in endothelial regulation of vascular tone. Annu Rev Pharmacol Toxicol 1995; 35: 235–55PubMedCrossRefGoogle Scholar
  63. 63.
    Pries AR, Secomb TW, Gaehtgens P. The endothelial surface layer. Pflugers Arch 2000; 440(5): 653–66PubMedCrossRefGoogle Scholar
  64. 64.
    Simionescu M, Gafencu A, Antohe F. Transcytosis of plasma macromolecules in endothelial cells: a cell biological survey. Microsc Res Tech 2002; 57(5): 269–88PubMedCrossRefGoogle Scholar
  65. 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): 32–42PubMedCrossRefGoogle Scholar
  66. 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): 105–12PubMedCrossRefGoogle Scholar
  67. 67.
    Alexander JS, Elrod JW. Extracellular matrix, junctional integrity and matrix metalloproteinase interactions in endothelial permeability regulation. J Anat 2002; 200(6): 561–74PubMedCrossRefGoogle Scholar
  68. 68.
    Bogatcheva NV, Garcia JG, Verin AD. Molecular mechanisms of thrombin-induced endothelial cell permeability. Biochemistry (Mosc) 2002; 67(1): 75–84CrossRefGoogle Scholar
  69. 69.
    Patel KD, Cuvelier SL, Wiehler S. Selectins: critical mediators of leukocyte recruitment. Semin Immunol 2002; 14(2): 73–81PubMedCrossRefGoogle Scholar
  70. 70.
    Toborek M, Kaiser S. Endothelial cell functions: relationship to atherogenesis. Basic Res Cardiol 1999; 94(5): 295–314PubMedCrossRefGoogle Scholar
  71. 71.
    Pearson JD. Endothelial cell function and thrombosis. Baillieres Best Pract Res Clin Haematol 1999; 12(3): 329–41PubMedCrossRefGoogle Scholar
  72. 72.
    Becker BF, Heindl B, Kupatt C, et al. Endothelial function and hemostasis. Z Kardiol 2000; 89(3): 160–7PubMedGoogle Scholar
  73. 73.
    Preissner KT, Nawroth PP, Kanse SM. Vascular protease receptors: integrating haemostasis and endothelial cell functions. J Pathol 2000; 190(3): 360–72PubMedCrossRefGoogle Scholar
  74. 74.
    Wei JY. Age and the cardiovascular system. N Engl J Med 1992; 327(24): 1735–9PubMedCrossRefGoogle Scholar
  75. 75.
    Folkow B, Svanborg A. Physiology of cardiovascular aging. Physiol Rev 1993; 73(4): 725–64PubMedGoogle Scholar
  76. 76.
    Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 1993; 73(2): 413–67PubMedGoogle Scholar
  77. 77.
    Gaballa MA, Jacob CT, Raya TE, et al. Large artery remodeling during aging: biaxial passive and active stiffness. Hypertension 1998; 32(3): 437–43PubMedCrossRefGoogle Scholar
  78. 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): 892–7PubMedCrossRefGoogle Scholar
  79. 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): S243–5PubMedGoogle Scholar
  80. 80.
    Kung CF, Luscher TF. Different mechanisms of endothelial dysfunction with aging and hypertension in rat aorta. Hypertension 1995; 25(2): 194–200PubMedCrossRefGoogle Scholar
  81. 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): 303–11PubMedCrossRefGoogle Scholar
  82. 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): H1843–54PubMedGoogle Scholar
  83. 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): 769–78PubMedCrossRefGoogle Scholar
  84. 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): H92–9PubMedGoogle Scholar
  85. 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): 77–81PubMedCrossRefGoogle Scholar
  86. 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): 471–6PubMedCrossRefGoogle Scholar
  87. 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): 1981–7PubMedCrossRefGoogle Scholar
  88. 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): 849–53PubMedCrossRefGoogle Scholar
  89. 89.
    Barton M, Cosentino F, Brandes RP, et al. Anatomic heterogeneity of vascular aging: role of nitric oxide and endothelin. Hypertension 1997; 30(4): 817–24PubMedCrossRefGoogle Scholar
  90. 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): 61–7PubMedCrossRefGoogle Scholar
  91. 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): H1138–43PubMedGoogle Scholar
  92. 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): H509–16PubMedGoogle Scholar
  93. 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): 1184–8PubMedCrossRefGoogle Scholar
  94. 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): 1039–43PubMedCrossRefGoogle Scholar
  95. 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): H2136–40PubMedGoogle Scholar
  96. 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): 265–74PubMedCrossRefGoogle Scholar
  97. 97.
    Taddei S, Virdis A, Ghiadoni L, et al. Menopause is associated with endothelial dysfunction in women. Hypertension 1996; 28(4): 576–82PubMedCrossRefGoogle Scholar
  98. 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): 113–8PubMedCrossRefGoogle Scholar
  99. 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): 276–82PubMedCrossRefGoogle Scholar
  100. 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): 215–20PubMedCrossRefGoogle Scholar
  101. 101.
    Woo KS, Chook P, Raitakari OT, et al. Westernization of Chinese adults and increased subclinical atherosclerosis. Arterioscler Thromb Vasc Biol 1999; 19(10): 2487–93PubMedCrossRefGoogle Scholar
  102. 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): 2896–901PubMedCrossRefGoogle Scholar
  103. 103.
    Jensen-Urstad K, Johansson J. Gender difference in age-related changes in vascular function. J Intern Med 2001; 250(1): 29–36PubMedCrossRefGoogle Scholar
  104. 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): 193–8PubMedGoogle Scholar
  105. 105.
    Taddei S, Virdis A, Ghiadoni L, et al. Age-related reduction of NO availability and oxidative stress in humans. Hypertension 2001; 38(2): 274–9PubMedCrossRefGoogle Scholar
  106. 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): 358–65PubMedGoogle Scholar
  107. 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): M121–7PubMedCrossRefGoogle Scholar
  108. 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): 595–600CrossRefGoogle Scholar
  109. 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): 1159–66PubMedCrossRefGoogle Scholar
  110. 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): 842–7PubMedCrossRefGoogle Scholar
  111. 111.
    Taddei S, Virdis A, Mattei P, et al. Hypertension causes premature aging of endothelial function in humans. Hypertension 1997; 29(3): 736–43PubMedCrossRefGoogle Scholar
  112. 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): 1796–804PubMedCrossRefGoogle Scholar
  113. 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): 1546–50PubMedCrossRefGoogle Scholar
  114. 114.
    Creager MA, Gallagher SJ, Girerd XJ, et al. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 1992; 90(4): 1248–53PubMedCrossRefGoogle Scholar
  115. 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): 139–55PubMedCrossRefGoogle Scholar
  116. 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): 1264–6PubMedGoogle Scholar
  117. 117.
    Vallance P, Leone A, Calver A, et al. Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis. J Cardiovasc Pharmacol 1992; 20Suppl. 12: S60–2PubMedCrossRefGoogle Scholar
  118. 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): 1842–7PubMedCrossRefGoogle Scholar
  119. 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): 2425–30PubMedCrossRefGoogle Scholar
  120. 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): 652–8PubMedCrossRefGoogle Scholar
  121. 121.
    Fleming I, Busse R. Signal transduction of eNOS activation. Cardiovasc Res 1999; 43(3): 532–41PubMedCrossRefGoogle Scholar
  122. 122.
    Cosentino F, Luscher TF. Tetrahydrobiopterin and endothelial nitric oxide synthase activity. Cardiovasc Res 1999; 43(2): 274–8PubMedCrossRefGoogle Scholar
  123. 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): 279–86PubMedCrossRefGoogle Scholar
  124. 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): 1731–44PubMedCrossRefGoogle Scholar
  125. 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): 643–8PubMedCrossRefGoogle Scholar
  126. 126.
    Stamler JS. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 1994; 78(6): 931–6PubMedCrossRefGoogle Scholar
  127. 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): C219–25PubMedGoogle Scholar
  128. 128.
    Stadtman ER. Protein oxidation and aging. Science 1992; 257(5074): 1220–4PubMedCrossRefGoogle Scholar
  129. 129.
    Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science 1996; 273(5271): 59–63PubMedCrossRefGoogle Scholar
  130. 130.
    Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev 1998; 78(2): 547–81PubMedGoogle Scholar
  131. 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): 149–58CrossRefGoogle Scholar
  132. 132.
    Vanhoutte PM. Endothelium-derived free radicals: for worse and for better. J Clin Invest 2001; 107(1): 23–5PubMedCrossRefGoogle Scholar
  133. 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): 113–21PubMedCrossRefGoogle Scholar
  134. 134.
    Varani J, Ward PA. Mechanisms of neutrophil-dependent and neutrophil-independent endothelial cell injury. Biol Signals 1994; 3(1): 1–14PubMedCrossRefGoogle Scholar
  135. 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): 1298–305PubMedCrossRefGoogle Scholar
  136. 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): 529–34PubMedCrossRefGoogle Scholar
  137. 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): 1347–50PubMedCrossRefGoogle Scholar
  138. 138.
    Szabo C. Cell death: the role of PARP. Boca Raton (FL): CRC Press, 2000CrossRefGoogle Scholar
  139. 139.
    Virag L, Szabo C. The therapeutic potential of poly (ADP-Ribose) polymerase inhibitors. Pharmacol Rev 2002; 54(3): 375–429PubMedCrossRefGoogle Scholar
  140. 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): 679–83PubMedCrossRefGoogle Scholar
  141. 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): 10203–8PubMedCrossRefGoogle Scholar
  142. 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): 684–91PubMedCrossRefGoogle Scholar
  143. 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): 659–64PubMedGoogle Scholar
  144. 144.
    Cooke JP. Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol 2000; 20(9): 2032–7PubMedCrossRefGoogle Scholar
  145. 145.
    Nakashima MVP. Decreased endothelium-dependent hyperpolarisation with aging and hypertension. In: PM Vanhoutte, editor. Endothelium-derived hyperpolarising factor. Amsterdam: Harwood Academic, 1996: 227–33Google Scholar
  146. 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): 595–602PubMedCrossRefGoogle Scholar
  147. 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: 323–32Google Scholar
  148. 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): 11–8PubMedGoogle Scholar
  149. 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): 210–6PubMedCrossRefGoogle Scholar
  150. 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): 542–8PubMedCrossRefGoogle Scholar
  151. 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): 804–10PubMedCrossRefGoogle Scholar
  152. 152.
    Stewart KG, Zhang Y, Davidge ST. Aging increases PGH-S-2-dependent vasoconstriction in rat mesenteric arteries. Hypertension 2000; 35(6): 1242–7PubMedCrossRefGoogle Scholar
  153. 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): R1625–31PubMedGoogle Scholar
  154. 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): 729–36PubMedCrossRefGoogle Scholar
  155. 155.
    Auch-Schwelk W, Katusic ZS, Vanhoutte PM. Nitric oxide inactivates endothelium-derived contracting factor in the rat aorta. Hypertension 1992; 19(5): 442–5PubMedCrossRefGoogle Scholar
  156. 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): S153–6PubMedGoogle Scholar
  157. 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): 908–13PubMedCrossRefGoogle Scholar
  158. 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–23SGoogle Scholar
  159. 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): 19–26PubMedCrossRefGoogle Scholar
  160. 160.
    Halcox JP, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002; 106(6): 653–8PubMedCrossRefGoogle Scholar
  161. 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): 2123–8PubMedCrossRefGoogle Scholar
  162. 162.
    Preli RB, Klein KP, Herrington DM. Vascular effects of dietary L-arginine supplementation. Atherosclerosis 2002; 162(1): 1–15PubMedCrossRefGoogle Scholar
  163. 163.
    Katusic ZS. Vascular endothelial dysfunction: does tetrahydrobiopterin play a role? Am J Physiol Heart Circ Physiol 2001; 281(3): H981–6PubMedGoogle Scholar
  164. 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): 187–94PubMedCrossRefGoogle Scholar
  165. 165.
    Heitzer T, Just H, Munzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation 1996; 94(1): 6–9PubMedCrossRefGoogle Scholar
  166. 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): 22–8PubMedCrossRefGoogle Scholar
  167. 167.
    May JM. How does ascorbic acid prevent endothelial dysfunction? Free Radic Biol Med 2000; 28(9): 1421–9PubMedCrossRefGoogle Scholar
  168. 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): 1806–14PubMedCrossRefGoogle Scholar
  169. 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): 193–9PubMedCrossRefGoogle Scholar
  170. 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): 75–9PubMedCrossRefGoogle Scholar
  171. 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): 2519–24PubMedCrossRefGoogle Scholar
  172. 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): 488–93PubMedCrossRefGoogle Scholar
  173. 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): 395–9PubMedCrossRefGoogle Scholar
  174. 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): 1179–87PubMedCrossRefGoogle Scholar
  175. 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): 486–90PubMedCrossRefGoogle Scholar
  176. 176.
    Dobrucki LW, Kalinowski L, Dobrucki IT, et al. Statin-stimulated nitric oxide release from endothelium. Med Sci Monit 2001; 7(4): 622–7PubMedGoogle Scholar
  177. 177.
    Sessa WC. Can modulation of endothelial nitric oxide synthase explain the vasculoprotective actions of statins? Trends Mol Med 2001; 7(5): 189–91PubMedCrossRefGoogle Scholar
  178. 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): 173–9PubMedCrossRefGoogle Scholar
  179. 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: 229–45PubMedCrossRefGoogle Scholar
  180. 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): 1639–49PubMedCrossRefGoogle Scholar
  181. 181.
    Takemoto M, Liao JK. Pleiotropic effects of 3-hydrox-y-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21(11): 1712–9PubMedCrossRefGoogle Scholar
  182. 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): 85–91CrossRefGoogle Scholar
  183. 183.
    Goto K. Basic and therapeutic relevance of endothelin-mediated regulation. Biol Pharm Bull 2001; 24(11): 1219–30PubMedCrossRefGoogle Scholar
  184. 184.
    Love MP, McMurray JJ. Endothelin receptor antagonists and cardiovascular diseases of aging. Drugs Aging 2001; 18(6): 425–40PubMedCrossRefGoogle Scholar
  185. 185.
    Ergul A. Endothelin-1 and endothelin receptor antagonists as potential cardiovascular therapeutic agents. Pharmacotherapy 2002; 22(1): 54–65PubMedCrossRefGoogle Scholar
  186. 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): 167–75PubMedCrossRefGoogle Scholar
  187. 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): 25–49PubMedGoogle Scholar
  188. 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): 108–12PubMedCrossRefGoogle Scholar
  189. 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): 305–10PubMedCrossRefGoogle Scholar
  190. 190.
    Goto K, Fujii K, Onaka U, et al. Angiotensin-converting enzyme inhibitor prevents age-related endothelial dysfunction. Hypertension 2000; 36(4): 581–7PubMedCrossRefGoogle Scholar
  191. 191.
    Kansui Y, Fujii K, Goto K, et al. Angiotensin II receptor antagonist improves age-related endothelial dysfunction. J Hypertens 2002; 20(3): 439–46PubMedCrossRefGoogle Scholar
  192. 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: S30–5PubMedGoogle Scholar
  193. 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): 1445–50PubMedCrossRefGoogle Scholar
  194. 194.
    Rajagopalan S, Brook R, Mehta RH, et al. Effect of losartan in aging-related endothelial impairment. Am J Cardiol 2002; 89(5): 562–6PubMedCrossRefGoogle Scholar
  195. 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): 847–55PubMedCrossRefGoogle Scholar
  196. 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): 2186–90PubMedCrossRefGoogle Scholar
  197. 197.
    Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340(23): 1801–11PubMedCrossRefGoogle Scholar
  198. 198.
    Yang S, Bae L, Zhang L. Estrogen increases eNOS and NOx release in human coronary artery endothelium. J Cardiovasc Pharmacol 2000; 36(2): 242–7PubMedCrossRefGoogle Scholar
  199. 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): 4108–13PubMedCrossRefGoogle Scholar
  200. 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): 2258–63PubMedCrossRefGoogle Scholar
  201. 201.
    Mendelsohn ME. Protective effects of estrogen on the cardiovascular system. Am J Cardiol 2002; 89 (12 Suppl.): 12E–7EPubMedCrossRefGoogle Scholar
  202. 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): H893–8PubMedGoogle Scholar
  203. 203.
    Arora S, Veves A, Caballaro AE, et al. Estrogen improves endothelial function. J Vasc Surg 1998; 27(6): 1141–6PubMedCrossRefGoogle Scholar
  204. 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): 2030–7PubMedCrossRefGoogle Scholar
  205. 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: 296–315PubMedCrossRefGoogle Scholar
  206. 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): 1158–63PubMedCrossRefGoogle Scholar
  207. 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): 1234–8PubMedCrossRefGoogle Scholar
  208. 208.
    Sarrel PM. The differential effects of oestrogens and progestins on vascular tone. Hum Reprod Update 1999; 5(3): 205–9PubMedCrossRefGoogle Scholar
  209. 209.
    Teoh H, Man RY. Progesterone modulates estradiol actions: acute effects at physiological concentrations. Eur J Pharmacol 1999; 378(1): 57–62PubMedCrossRefGoogle Scholar
  210. 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): 467–70PubMedCrossRefGoogle Scholar
  211. 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): 49–57PubMedCrossRefGoogle Scholar
  212. 212.
    Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: scientific review. JAMA 2002; 288(7): 872–81PubMedCrossRefGoogle Scholar
  213. 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): 1955–61PubMedCrossRefGoogle Scholar
  214. 214.
    Clarkson P, Montgomery HE, Mullen MJ, et al. Exercise training enhances endothelial function in young men. J Am Coll Cardiol 1999; 33(5): 1379–85PubMedCrossRefGoogle Scholar
  215. 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): 233–9PubMedCrossRefGoogle Scholar
  216. 216.
    Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996; 93(2): 210–4PubMedCrossRefGoogle Scholar
  217. 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): 137–43PubMedCrossRefGoogle Scholar
  218. 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): 454–60PubMedCrossRefGoogle Scholar
  219. 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): 1933–40PubMedGoogle Scholar
  220. 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): 2709–15PubMedCrossRefGoogle Scholar
  221. 221.
    Griffin KL, Laughlin MH, Parker JL. Exercise training improves endothelium-mediated vasorelaxation after chronic coronary occlusion. J Appl Physiol 1999; 87(5): 1948–56PubMedGoogle Scholar
  222. 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): 2951–7PubMedCrossRefGoogle Scholar
  223. 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): H1441–6PubMedGoogle Scholar
  224. 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): 194–8PubMedCrossRefGoogle Scholar
  225. 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): 1393–8PubMedCrossRefGoogle Scholar
  226. 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): 1219–24PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Biochemisches Institut, Fachbereich HumanmedizinJustus Liebig UniversitätGiessenGermany
  2. 2.Laboratoire de Pharmacologie et Physico-Chimie des Interactions Cellulaires et MoléculairesIllkirchFrance

Personalised recommendations