Direct Actions of Estrogen on Vascular Cells Ameliorates Response to Injury

  • D. W. Losordo
Part of the Medical Science Symposia Series book series (MSSS, volume 13)


In spite of significant advances in technique and adjunctive medical treatment, restenosis after percutaneous coronary revascularization remains a major problem. Moreover, women have fared comparatively poorly after percutaneous transluminal coronary angioplasty (PTCA) with less long-term relief of symptoms and a trend towards reduced survival compared to men [1]. Interestingly, two recent retrospective studies have suggested that women who took estrogen replacement therapy (ERT) after their angioplasty had less restenosis [2] and better long-term outcome [3] than their nonestrogen taking counterparts.


Fibrinogen Level Arterioscler Thromb Vasc Biol Plasma Fibrinogen Level Fibrinogen Gene Coronary Heart Disease Development 


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  1. 1.
    Bell MR, Grill DE, Garratt KN, Berger PB, Gersh BJ, Holmes DR. Long-term outcome of women compared with men after successful coronary angioplasty. Circulation 1995;91: 2876–80.PubMedGoogle Scholar
  2. 2.
    O’Brien JE, Peterson ED, Keeler GP, et al. Relation between estrogen replacement therapy and restenosis after percutaneous coronary interventions. JACCb 1996;28:1111–18.Google Scholar
  3. 3.
    O’Keefe JH, Kim SC, Hall RR, Cochran VC, Lawhorn SL, McCallister BD. Estrogen replacement therapy after coronary angioplasty in women. J Am Coll Cardiol 1997;29:1–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Williams JK, Wagner JD, Li Z, Golden DL, Adams MR. Tamoxifen inhibits arterial accumulation of LDL degradation products and progression of coronary artery atherosclerosis in monkeys. Arterioscler Thromb Vasc Biol 1997;17:403–8.PubMedGoogle Scholar
  5. 5.
    Bjarnason NH, Haarbo J, Byjalsen I, Kauffman RF, Christiansen, C. Raloxifen inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits. Circulation 1997;96:1964–69.PubMedGoogle Scholar
  6. 6.
    Holm P, Shalmi M, Korsgaard N, Guldhammer B, Skouby SV, Stender S. A partial estrogen receptor agonist with strong antiatherogenic properties without noticeable effect on reproductive tissue in cholesterol-fed female and male rabbits. Arterioscler Thromb Vasc Biol 1997;17:2264–72.PubMedGoogle Scholar
  7. 7.
    Wantanabe T, Inoue S, Ogawa S, et al. Agonistic effect of tamoxifen is dependent on cell type, ERE-promoter context, and estrogen receptor subtype: Functional difference between estrogen receptors a and b. Biochem & Biophys Res Comm 1997;236:140–45.CrossRefGoogle Scholar
  8. 8.
    Paech K, Webb P, Kuiper GGJM, et al. Differential ligand activation of estrogen receptors ERa and ERb at AP1 sites. Science 1997;277:1508–10.PubMedCrossRefGoogle Scholar
  9. 9.
    Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. NEJM 1997;337:1641–47.PubMedCrossRefGoogle Scholar
  10. 10.
    Losordo DW, Kearney M, Kim EA, Jekanowski J, Isner JM. Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation 1994;89:1501–10.PubMedGoogle Scholar
  11. 11.
    Rubayni GM, Freay AD, Kauser K, et al. Vascular estrogen receptors and endothelium-derived nitric oxide production in the mouse aorta. J Clin Invest 1997;99:2429–37.Google Scholar
  12. 12.
    Karas RH, Patterson BL, Mendelsohn ME. Human vascular smooth muscle cells contain functional estrogen receptor. Circulation 1994;89:1943–50.PubMedGoogle Scholar
  13. 13.
    Kearney M, Pieczek A, Haley L, et al. Histopathology of in-stent restenosis in patients with peripheral vascular disease. Circulation 1997;95:1998–2002.PubMedGoogle Scholar
  14. 14.
    Mecander PJ, Roubin GS, Agrawal SK, Cannon AD, Dean LS, Baxley WA. Balloon angioplasty for treatment of in-stent restenosis: Feasibility, safety and efficacy. Cathet Cardiovasc Diagn 1994;32:125–31.CrossRefGoogle Scholar
  15. 15.
    Bowerman RE, Pinkerton CA, Kirk B, Waller BF. Disruption of a coronary stent during atherectomy for restenosis. Cathet Cardiovasc Design 1993;71:364–66.Google Scholar
  16. 16.
    O’Brien ER, Alpers CE, Stewart DK, et al. Proliferation in primary and restenotic coronary atherectomy tissue: Implications for antiproliferative therapy. Circ Res 1993;3:223–31.Google Scholar
  17. 17.
    Pickering JG, Bacha P, Weir L, Jekanowski J, Nichols JC, Isner JM. Prevention of smooth muscle cell outgrowth from human atherosclerotic plaque by a recombinant fusion protein specific for epidermal growth factor receptor. J Clin Invest 1993;91:724–29.PubMedGoogle Scholar
  18. 18.
    Rekhter M, Ferguson SN, Gordon D. Cell proliferation in human arteriovenous fistulas used for hemodialysis. Arteriosclerosis and Thrombosis 1993;13:609–17.PubMedGoogle Scholar
  19. 19.
    Spyridopoulos I, Losordo DW. Cardiovascular estrogen receptors regulate vascular smooth muscle cell proliferation. In: Forte TM, editor. Hormonal, metabolic, and cellular influences on cardiovascular disease in women. Armonk, NY: Futura Publishing Company, Inc., 1997: 71–97.Google Scholar
  20. 20.
    Kim-Schuize S, McGowan KA, Hubchak SC, et al. Expression of an estrogen receptor by human coronary artery and umbilical vein endothelial cells. Circulation 1996;94:1402–7.Google Scholar
  21. 21.
    Venkov CD, Rankin AB, Vaughan DE. Identification of authentic estrogen receptor in cultured endothelial cells. Circulation 1996;94:727–33.PubMedGoogle Scholar
  22. 22.
    Spyridopoulos I, Sullivan A, Kearney M, Isner JM, Losordo DW. Estrogen receptor mediated inhibition of human endothelial cell apoptosis: Estradiol as a survival factor. Circulation 1997; 95:1505–14.PubMedGoogle Scholar
  23. 23.
    Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature 1993; 362:801–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Warner SJC, Libby P. Human vascular smooth muscle cells. Target for and source of tumor necrosis factor. J Immunol 1989;142:100–109.PubMedGoogle Scholar
  25. 25.
    Barath P, Fishbein CM, Cao J, Berenson J, Helfant RH, Forrester JS. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol 1990a;65:297–302.PubMedCrossRefGoogle Scholar
  26. 26.
    Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS. Tumor necrosis factor gene expression in human vascular intimal smooth muscle cells detected by in situ hybridization. Am J Pathol 1990b;137:503–9.PubMedGoogle Scholar
  27. 27.
    Clausell N, Correa de Lima V, Molossi S, et al. Expression of tumor necrosis factor and accumulation of fibronectin in coronary artery restenosis lesions retrieved by atherectomy. Br Heart J 1995;73:534–39.PubMedGoogle Scholar
  28. 28.
    Hancock WW, Adams DH, Wyner LR, Sayegh MH, Karnovsky MJ. (1994). CD4+ mononuclear cells induce cytokine expression, vascular smooth muscle cell proliferation, and arterial occlusion after endothelial injury. Am J Pathol 1994;145:1008–14.PubMedGoogle Scholar
  29. 29.
    Tanaka H, Sukhova G, Schwartz D, Libby P. Proliferating arterial smooth muscle cells after balloon injury express TNF-a but not interleukin-1 or basic fibroblast growth factor. Arterioscler Thromb Vasc Biol 1996;16:12–18.PubMedGoogle Scholar
  30. 30.
    Tanaka H, Swanson SJ, Sukhova G, Schoen FJ, Libby P. Smooth muscle cells of the coronary arterial tunica media express tumor necrosis factor-a and proliferate during acute rejection of rabbit cardiac allografts. Am J Pathol 1995; 147:617–26.PubMedGoogle Scholar
  31. 31.
    Clausell N, Molossi S, Sett S, Rabinovitch M. In vivo blockade of tumor necrosis factor-a in cholesterol-fed rabbits after cardiac transplant inhibits acute coronary artery neointimal formation. Circulation 1994;89:2768–79.PubMedGoogle Scholar
  32. 32.
    Duan H, Chinnaiyan AM, Hudson PL, Wing JP, He WW, Dixit VM. ICE-LAP3, a novel mammalian homologue of the caenorhabditis elegans cell death protein ced-3 is activated during fas-and tumor necrosis factor-induced apoptosis. J Biol Chem 1996;271:1621–25.PubMedCrossRefGoogle Scholar
  33. 33.
    Geng YJ, Libby P. Evidence for apoptosis in advanced human atheroma. Am J Pathol 1995;147:251–66.PubMedGoogle Scholar
  34. 38.
    Chen SJ, Li H, Durand J, Oparil S, Chen YF. Estrogen reduces myointimal proliferation after balloon injury of rat carotid artery. Circulation 1996;93:577–84.PubMedGoogle Scholar
  35. 39.
    Hanke H, Hanke S, Finking, G, et al. Different effects of estrogen and progesterone on experimental atherosclerosis in female versus male rabbits. Circulation 1996;94:175–81.PubMedGoogle Scholar
  36. 34.
    Tepper CG, Jayadev S, Liu B, et al. Role of ceramide as an endogenous mediator of Fas-induced cytotoxicity. Proc Natl Acad Sci USA 1995;92:8443–47.PubMedCrossRefGoogle Scholar
  37. 35.
    Asahara T, Bauters C, Pastore C, et al. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimai hyperplasia in balloon-injured rat carotid artery. Circulation 1995;91:2793–2801.PubMedGoogle Scholar
  38. 36.
    Krasinski K, Spyridopoulos I, Asahara T, van der Zee R, Isner JM, Losordo DW. Estradiol accelerates functional endothelial recovery after arterial injury. Circulation 1997;95:1768–72.PubMedGoogle Scholar
  39. 37.
    Wolinsky H. Effect of estrogen and progestogen treatment on the response of the aorta of male rats to hypertension. Circ Res 1972;30:341–49.PubMedGoogle Scholar
  40. 40.
    Sullivan TR, Karas RH, Aronovitz M, et al. Estrogen inhibits the response-to-injury in a mouse carotid artery model. J Clin Invest 1995;95:2482–88.CrossRefGoogle Scholar
  41. 41.
    Foegh ML, Asotra S, Howell MH, Ramwell PW. Estradiol inhibition of arterial neointimal hyperplasia after balloon injury. J Vase Surgery 1994;19:722–26.Google Scholar
  42. 42.
    Morales DE, McGowan KA, Grant DS, et al. Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 1995; 91:755–63.PubMedGoogle Scholar
  43. 43.
    White CR, Shelton J, Chen SJ, et al. Estrogen restores endothelial cell function in an experimental model of vascular injury. Circulation 1997;96:1624–30.PubMedGoogle Scholar
  44. 44.
    VanBelle E, Fermin OT, Chen D, Maillard L, Kearney M, Isner JM. Passivation of metallic stents after arterial gene transfer of phVEGF165 inhibits thrombus formation and intimal thickening. J Am Coll Cardiol 1997;29:1371–79.CrossRefGoogle Scholar
  45. 45.
    Karas RH, Bieber HE, Baur WE, Mendelsohn ME. Estrogen enhances vascular endothelial growth factor (VEGF) gene expression in human vascular smooth muscle cells. Circulation 1996;94:1–595.(Abstract).Google Scholar

Copyright information

© Kluwer Academic Publishers and Fondazione Giovanni Lorenzini 1999

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  • D. W. Losordo

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