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Molecular mechanisms of estrogen actions on the vasculature

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Journal of Nuclear Cardiology Aims and scope

Summary

In summary, clinical and animal studies demonstrate that the effects of estrogen in the cardiovascular system protect against the development of histologic and clinical atherosclerosis. However, because estrogen affects so many cellular processes (Figure 4), there are many known adverse effects, including oncogenic and potential negative consequences on the vasculature, including procoagulant and plaque-destabilizing effects. Selective estrogen receptor modulators may allow us to target specific pathways that selectively and favorably effect beneficial responses. However, we must first gain a better understanding of the molecular mechanisms by which estrogen induces cellular signals, both genomic and nongenomic, before we can take full advantage of selective estrogen receptor modulators. As our ability to selectively modulate vascular responses to injury improves, it will be imperative that we have the ability to assess vascular structure, function and pathology with more practical, logistically accessible and biologically targeted approaches than those currently available. Such tools will allow us to test a broad spectrum of agents aimed at pharmacologic therapy for vascular disease.

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References

  1. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial. JAMA 1995;273:199–208.

    Article  Google Scholar 

  2. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al, for the HERS Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605–13.

    Article  PubMed  CAS  Google Scholar 

  3. The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998;19:61–109.

    Article  Google Scholar 

  4. Oparil S. Hormones and vasoprotection. Hypertension 1999;33:170–6.

    PubMed  CAS  Google Scholar 

  5. Rossouw J. Estrogens for prevention of coronary heart disease: putting the brakes on the bandwagon. Circulation 1996;94:2982–5.

    PubMed  CAS  Google Scholar 

  6. Guetta V, Cannon RO. Cardiovascular effects of estrogen and lipid-lowering therapies in postmenopausal women. Circulation 1996;93: 1928–37.

    PubMed  CAS  Google Scholar 

  7. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesonon K, et al. The nuclear receptor superfamily: the second decade. Cell 1995;83:835–9.

    Article  PubMed  CAS  Google Scholar 

  8. Brown M. Estrogen receptor molecular biology. Hematol/Oncol Clin North Am 1994;8:101–12.

    CAS  Google Scholar 

  9. Kato S, Tora L, Yamauchi J, Bellard M, Chambon P. A far upstream estrogen response element of the ovalbumin gene contains several halfpalindromic 5′-TAGACC-3′ motifs acting synergistically. Cell 1992;68:731–42.

    Article  PubMed  CAS  Google Scholar 

  10. Brown M, Sharp PA. Human estrogen receptor forms multiple protein- DNA complexes. J Biol Chem 1990;265:11238–43.

    PubMed  CAS  Google Scholar 

  11. Tremblay A, Tremblay GB, Labrie F, Giguere V. Ligand-independent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1. Mol Cell 1999;3:513–9.

    Article  PubMed  CAS  Google Scholar 

  12. Smith CL. Cross-talk between peptide growth factor and estrogen receptor signaling pathways. Biol Reprod 1998;58:627–32.

    Article  PubMed  CAS  Google Scholar 

  13. Robinson LJ, Weremowicz C, Morton CC, Michel T. Isolation and chromosomal localization of the human eNOS gene. Genomics 1994;19:350–7.

    Article  PubMed  CAS  Google Scholar 

  14. Caulin-Glaser T, Garcia-Cardena G, Sarrel P, Sessa WC, Bender JR. 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. Circ Res 1997;81:885–92.

    PubMed  CAS  Google Scholar 

  15. Russell K, Haynes M, Sinha D, Clerisme E, Bender J. Human vascular endothelial cells contain membrane binding sites for estradiol, which mediate rapid intracellular signaling. Proc Natl Acad Sci USA 2000;97:5930–5.

    Article  PubMed  CAS  Google Scholar 

  16. Greene GL, Gilna P, Waterfield M, Baker A, Hort Y, Shine J. Sequence and expression of human estrogen receptor complementary DNA. Science 1986;231:1150–4.

    Article  PubMed  CAS  Google Scholar 

  17. Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P, Chambon P. Human oestrogen receptor cDNA sequence expression and homology to v-erb-A. Nature 1986;320:134–9.

    Article  PubMed  CAS  Google Scholar 

  18. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996;93:5925–30.

    Article  PubMed  CAS  Google Scholar 

  19. Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F, et al. Cloning, chromosomal localization and functional analysis of the murine estrogen receptor beta. Mol Endocrinol 1997;11:353–65.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  21. Brzozowski AM, Pike ACW, Dauter Z, Hubbard RE, Bonn T, Engstrom O, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997;389:753–8.

    Article  PubMed  CAS  Google Scholar 

  22. Cowley SM, Hoare S, Mosselman S, Parker MG. Estrogen receptors alpha and beta form heterodimers on DNA. J Biol Chem 1997;272:19858–62.

    Article  PubMed  CAS  Google Scholar 

  23. Pace P, Taylor J, Suntharalingam S, Coombes RC, Ali S. Human estrogen receptor beta binds DNA in a manner similar to and dimerizes with estrogen receptor alpha. J Biol Chem 1997;272: 25832–8.

    Article  PubMed  CAS  Google Scholar 

  24. Venkov CD, Rankin AB, Vaughan DE. Identification of authentic estrogen receptor in cultured endothelial cells. A potential mechanism for steroid hormone regulation of endothelial function. Circulation 1996;94:727–33.

    PubMed  CAS  Google Scholar 

  25. Kim-Schulze S, McGowan KA, Hubchak SC, Cid MC, Martin MB, Kleinman HK, et al. Expression of an estrogen receptor by human coronary artery and umbilical vein endothelial cells. Circulation 1996;94:1402–7.

    PubMed  CAS  Google Scholar 

  26. Karas RH, Patterson BL, Mendelsohn ME. Human vascular smooth muscle cells contain functional estrogen receptor. Circulation 1994;89:1943–50.

    PubMed  CAS  Google Scholar 

  27. Lindner V, Kim SK, Karas RH, Kuiper GG, Gustafsson JA, Mendelsohn ME. Increased expression of estrogen receptor-beta mRNA in male blood vessels after vascular injury. Circ Res 1998;83:224–9.

    PubMed  CAS  Google Scholar 

  28. Makela S, Savolainen H, Avik E, Myllarniemi M, Strauss L, Taskinen E, et al. Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors alpha and beta. Proc Natl Acad Sci USA 1999;96:7077–82.

    Article  PubMed  CAS  Google Scholar 

  29. Lantin-Hermoso RL, Rosenfeld CR, Yuhanna IS, German Z, Chen Z, Shaul PW. Estrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothelium. Am J Physiol 1997;273: L119–26.

    PubMed  CAS  Google Scholar 

  30. Busconi L, Michel T. Endothelial nitric oxide synthase. N-terminal myristoylation determines subcellular localization. J Biol Chem 1993;268:8410–3.

    PubMed  CAS  Google Scholar 

  31. Garcia-Cardena G, Oh P, Liu J, Schnitzer JE, Sessa WC. Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc Natl Acad Sci USA 1996;93:6448–53.

    Article  PubMed  CAS  Google Scholar 

  32. Sessa WC, Garcia-Cardena G, Liu J, Keh A, Pollock JS, Bradley J, et al. The Golgi association of endothelial nitric oxide synthase is necessary for the efficient synthesis of nitric oxide. J Biol Chem 1995; 270:17641–4.

    Article  PubMed  CAS  Google Scholar 

  33. Liu J, Garcia-Cardena G, Sessa WC. Palmitoylation of endothelial nitric oxide synthase is necessary for optimal stimulated release of nitric oxide: implications for caveolae localization. Biochemistry 1996;35:13277–81.

    Article  PubMed  CAS  Google Scholar 

  34. Garcia-Cardena G, Fan R, Stern DF, Liu J, Sessa WC. Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1. J Biol Chem 1996;271:27237–40.

    Article  PubMed  CAS  Google Scholar 

  35. Shaul PW, Smart EJ, Robinson LJ, German Z, Yuhanna IS, Ying Y, et al. Acylation targets endothelial nitric-oxide synthase to plasmalemmal caveolae. J Biol Chem 1996;271:6518–22.

    Article  PubMed  CAS  Google Scholar 

  36. Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Schmidt K, et al. Pteridine biosynthesis in human endothelial cells. Impact on nitric oxide-mediated formation of cyclic GMP. J Biol Chem 1993;268:1842–6.

    PubMed  CAS  Google Scholar 

  37. Forstermann U, Pollock JS, Schmidt HH, Heller M, Murad F. Calmodulin-dependent endothelium-derived relaxing factor/nitric oxide synthase activity is present in the particulate and cytosolic fractions of bovine aortic endothelial cells. Proc Natl Acad Sci USA 1991;88:1788–92.

    Article  PubMed  CAS  Google Scholar 

  38. Garcia-Cardena G, Martasek P, Masters BS, Skidd PM, Couet J, Li S, et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem 1997;272:25437–40.

    Article  PubMed  CAS  Google Scholar 

  39. Garcia-Cardena G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, et al. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 1998;392:821–4.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  41. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Aktdependent phosphorylation. Nature 1999;399:601–5.

    Article  PubMed  CAS  Google Scholar 

  42. McCabe TJ, Fulton D, Roman LJ, Sessa WC. Enhanced electron flux and reduced calmodulin dissociation may explain “calcium-independent” eNOS activation by phosphorylation. J Biol Chem 2000;275:6123–8.

    Article  PubMed  CAS  Google Scholar 

  43. Russell KS, Haynes MP, Caulin-Glaser T, Rosneck J, Sessa WC, Bender J. Estrogen stimulates heat shock protein 90 binding to endothelial nitric oxide synthase in human vascular endothelial cells. J Biol Chem 2000;275:5026–30.

    Article  PubMed  CAS  Google Scholar 

  44. Nishida CR, Ortiz de Montellano PR. Autoinhibition of endothelial nitric-oxide synthase. Identification of an electron transfer control element. J Biol Chem 1999;274:14692–8.

    Article  PubMed  CAS  Google Scholar 

  45. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999;399:597–601.

    Article  PubMed  CAS  Google Scholar 

  46. MacRitchie AN, Jun SS, Chen Z, German Z, Yuhanna IS, Sherman TS, et al. Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ Res 1997;81:355–62.

    PubMed  CAS  Google Scholar 

  47. Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T. Upregulation of nitric oxide synthase by estradiol in human aortic endothelial cells. FEBS Lett 1995;360:291–3.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  49. Radomski MW, Palmer RM, Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 1990;87:5193–7.

    Article  PubMed  CAS  Google Scholar 

  50. Garg UC, Hasid A. Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1774–7.

    Article  PubMed  CAS  Google Scholar 

  51. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991;88:4651–5.

    Article  PubMed  CAS  Google Scholar 

  52. Darkow D, Lu L, White RE. Estrogen relaxation of coronary artery smooth muscle is mediated by nitric oxide and cGMP. Am J Physiol 1997;272:H2765–73.

    PubMed  CAS  Google Scholar 

  53. Randomski MW, Palmer RM, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 1987;2:1057–8.

    Article  Google Scholar 

  54. Lou H, Zhao Y, Delafontaine P, Kodama T, Katz N, Ramwell PW, et al. Estrogen effects on insulin-like growth factor-I (IGF-I)-induced cell proliferation and IGF-I expression in native and allograft vessels. Circulation 1997;96:927–33.

    PubMed  CAS  Google Scholar 

  55. Kolodgie FD, Jacob A, Wilson PS, Carlson GC, Farb A, Verma A, et al. Estradiol attenuates directed migration of vascular smooth muscle cells in vitro. Am J Pathol 1996;148:969–76.

    PubMed  CAS  Google Scholar 

  56. Cybulsky MI, Gimbrone MA. Endothelial expression of mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991;251:788–91.

    Article  PubMed  CAS  Google Scholar 

  57. Caulin-Glaser T, Watson CA, Pardi R, Bender JR. Effects of 17betaestradiol on cytokine-induced endothelial cell adhesion molecule expression. J Clin Invest 1996;98:36–42.

    Article  PubMed  CAS  Google Scholar 

  58. Nathan L, Pervin S, Singh R, Rosenfeld M, Chaudhuri G. Estradiol inhibits leukocyte adhesion and transendothelial migration in rabbits in vivo: possible mechanisms for gender differences in atherosclerosis. Circ Res 1999;85:377–85.

    PubMed  CAS  Google Scholar 

  59. Pervin S, Singh R, Rosenfeld ME, Navab M, Chaudhuri G, Nathan L. Estradiol suppresses MCP-1 expression in vivo: implications for atherosclerosis. Arterioscler Thromb Vasc Biol 1998;18:1575–82.

    PubMed  CAS  Google Scholar 

  60. Morales DE, McGowan KA, Grant D, Maheshwari S, Bhartiya D, Cid MC, et al. Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 1995;91:755–63.

    PubMed  CAS  Google Scholar 

  61. 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.

    PubMed  CAS  Google Scholar 

  62. White CR, Shelton J, Chen SJ, Darley-Usmar V, Allen L, Nabors C, et al. Estrogen restores endothelial cell function in an experimental model of vascular injury. Circulation 1997;96:1624–30.

    PubMed  CAS  Google Scholar 

  63. Sypridopoulos I, Sullivan AB, 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.

    Google Scholar 

  64. Sullivan TR, Jr, Karas RH, Aronovitz M, Faller GT, Ziar JP, et al. Estrogen inhibits the response-to-injury in a mouse carotid artery model. J Clin Invest 1995;96:2482–8.

    Article  PubMed  CAS  Google Scholar 

  65. Iafrati MD, Karas RH, Aronovitz M, Kim S, Sullivan TR, Jr, et al. Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nat Med 1997;3:545–8.

    Article  PubMed  CAS  Google Scholar 

  66. Krege JH, Hodgin JB, Couse JF, Enmark E,Warner M, Mahler JF, et al. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci USA 1998;95:15677–82.

    Article  PubMed  CAS  Google Scholar 

  67. Karas RH, Hodgin JB, Kwoun M, Krege JH, Aronovitz M, Mackey W, Gustafsson JA, et al. Estrogen inhibits the vascular injury response in estrogen receptor beta-deficient female mice. Proc Natl Acad Sci USA 1999;96:15133–6.

    Article  PubMed  CAS  Google Scholar 

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  1. Divisions of Cardiovascular Medicine and Molecular Cardiobiology, Boyer Center for Molecular Medicine, 454C Yale University School of Medicine, 259 Congress Ave, 06536-0812, New Haven, CT

    M. Page Haynes, Kerry Strong Russell & Jeffrey R. Bender

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  1. M. Page Haynes
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  2. Kerry Strong Russell
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Correspondence to Jeffrey R. Bender.

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Haynes, M.P., Russell, K.S. & Bender, J.R. Molecular mechanisms of estrogen actions on the vasculature. J Nucl Cardiol 7, 500–508 (2000). https://doi.org/10.1067/mnc.2000.109958

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