Download PDF
Semin Reprod Med 2012; 30(01): 46-61
DOI: 10.1055/s-0031-1299597
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Estrogen Receptor-α and Estrogen Receptor-β in the Uterine Vascular Endothelium during Pregnancy: Functional Implications for Regulating Uterine Blood Flow

Mayra B. Pastore
1   Departments of Obstetrics/Gynecology, Perinatal Research Laboratories
*   Both authors have contributed equally to this manuscript.
,
Sheikh O. Jobe
1   Departments of Obstetrics/Gynecology, Perinatal Research Laboratories
*   Both authors have contributed equally to this manuscript.
,
Jayanth Ramadoss
1   Departments of Obstetrics/Gynecology, Perinatal Research Laboratories
,
Ronald R. Magness
1   Departments of Obstetrics/Gynecology, Perinatal Research Laboratories
2   Pediatrics
3   Animal Sciences, University of Wisconsin-Madison, Madison, Wisconsin
› Author Affiliations
Further Information

Publication History

Publication Date:
23 January 2012 (online)

    Permissions and Reprints

Abstract

The steroid hormone estrogen and its classical estrogen receptors (ERs), ER-α and ER-β, have been shown to be partly responsible for the short- and long-term uterine endothelial adaptations during pregnancy. The ER-subtype molecular and structural differences coupled with the differential effects of estrogen in target cells and tissues suggest a substantial functional heterogeneity of the ERs in estrogen signaling. In this review we discuss (1) the role of estrogen and ERs in cardiovascular adaptations during pregnancy, (2) in vivo and in vitro expression of ERs in uterine artery endothelium during the ovarian cycle and pregnancy, contrasting reproductive and nonreproductive arterial endothelia, (3) the structural basis for functional diversity of the ERs and estrogen subtype selectivity, (4) the role of estrogen and ERs on genomic responses of uterine artery endothelial cells, and (5) the role of estrogen and ERs on nongenomic responses in uterine artery endothelia. These topics integrate current knowledge of this very rapidly expanding scientific field with diverse interpretations and hypotheses regarding the estrogenic effects that are mediated by either or both ERs and their relationship with vasodilatory and angiogenic vascular adaptations required for modulating the dramatic physiological rises in uteroplacental perfusion observed during normal pregnancy.

Keywords

estrogen receptor - uterine endothelium - vasodilatation - angiogenesis - pregnancy
 

  • References

  • 1 Meyers MJ, Sun J, Carlson KE, Marriner GA, Katzenellenbogen BS, Katzenellenbogen JA. Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J Med Chem 2001; 44 (24) 4230-4251
    CrossrefPubMedGoogle Scholar
  • 2 Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340 (23) 1801-1811
    CrossrefPubMedGoogle Scholar
  • 3 Chambliss KL, Yuhanna IS, Mineo C , et al. Estrogen receptor alpha and endothelial nitric oxide synthase are organized into a functional signaling module in caveolae. Circ Res 2000; 87 (11) E44-E52
    CrossrefPubMedGoogle Scholar
  • 4 Chen DB, Bird IM, Zheng J, Magness RR. Membrane estrogen receptor-dependent extracellular signal-regulated kinase pathway mediates acute activation of endothelial nitric oxide synthase by estrogen in uterine artery endothelial cells. Endocrinology 2004; 145 (1) 113-125
    PubMedGoogle Scholar
  • 5 Magness RR, Phernetton TM, Gibson TC, Chen DB. Uterine blood flow responses to ICI 182 780 in ovariectomized oestradiol-17beta-treated, intact follicular and pregnant sheep. J Physiol 2005; 565 (Pt 1) 71-83
    CrossrefPubMedGoogle Scholar
  • 6 Magness RR, Phernetton TM, Zheng J. Systemic and uterine blood flow distribution during prolonged infusion of 17beta-estradiol. Am J Physiol 1998; 275 (3 Pt 2) H731-H743
    PubMedGoogle Scholar
  • 7 Rosenfeld CR, Cox BE, Roy T, Magness RR. Nitric oxide contributes to estrogen-induced vasodilation of the ovine uterine circulation. J Clin Invest 1996; 98 (9) 2158-2166
    CrossrefPubMedGoogle Scholar
  • 8 Rosenfeld CR. Distribution of cardiac output in ovine pregnancy. Am J Physiol 1977; 232 (3) H231-H235
    PubMedGoogle Scholar
  • 9 Lang U, Baker RS, Braems G, Zygmunt M, Künzel W, Clark KE. Uterine blood flow—a determinant of fetal growth. Eur J Obstet Gynecol Reprod Biol 2003; 110 (Suppl 1) S55-S61
    CrossrefPubMedGoogle Scholar
  • 10 Magness RR, Rosenfeld CR. The role of steroid hormones in the control of uterine blood flow. In: Rosenfeld CR, ed. The Uterine Circulation. Reproductive and Perinatal Medicine. Ithaca, NY: : Perinatology Press; ; 1989. 10. 239-271
    Google Scholar
  • 11 Ford SP. Control of uterine and ovarian blood flow throughout the estrous cycle and pregnancy of ewes, sows and cows. J Anim Sci 1982; 55 (Suppl 2) 32-42
    PubMedGoogle Scholar
  • 12 Ford SP, Christenson RK. Blood flow to uteri of sows during the estrous cycle and early pregnancy: local effect of the conceptus on the uterine blood supply. Biol Reprod 1979; 21 (3) 617-624
    CrossrefPubMedGoogle Scholar
  • 13 Gibson TC, Phernetton TM, Wiltbank MC, Magness RR. Development and use of an ovarian synchronization model to study the effects of endogenous estrogen and nitric oxide on uterine blood flow during ovarian cycles in sheep. Biol Reprod 2004; 70 (6) 1886-1894
    CrossrefPubMedGoogle Scholar
  • 14 Greiss Jr FC, Anderson SG. Uterine vescular changes during the ovarian cycle. Am J Obstet Gynecol 1969; 103 (5) 629-640
    PubMedGoogle Scholar
  • 15 Harvey CA, Owen DA. Changes in uterine and ovarian blood flow during the oestrous cycle in rats. J Endocrinol 1976; 71 (3) 367-369
    CrossrefPubMedGoogle Scholar
  • 16 Greiss Jr FC, Anderson SG. Effect of ovarian hormones on the uterine vascular bed. Am J Obstet Gynecol 1970; 107 (6) 829-836
    PubMedGoogle Scholar
  • 17 Rosenfeld CR, Killam AP, Battaglia FC, Makowski EL, Meschia G. Effect of estradiol-17 on the magnitude and distribution of uterine blood flow in nonpregnant, oophorectomized ewes. Pediatr Res 1973; 7 (3) 139-148
    CrossrefPubMedGoogle Scholar
  • 18 Rosenfeld CR, Morriss Jr FH, Makowski EL, Meschia G, Battaglia FC. Circulatory changes in the reproductive tissues of ewes during pregnancy. Gynecol Invest 1974; 5 (5-6) 252-268
    CrossrefPubMedGoogle Scholar
  • 19 Miller SL, Jenkin G, Walker DW. Effect of nitric oxide synthase inhibition on the uterine vasculature of the late-pregnant ewe. Am J Obstet Gynecol 1999; 180 (5) 1138-1145
    CrossrefPubMedGoogle Scholar
  • 20 Van Buren GA, Yang DS, Clark KE. Estrogen-induced uterine vasodilatation is antagonized by L-nitroarginine methyl ester, an inhibitor of nitric oxide synthesis. Am J Obstet Gynecol 1992; 167 (3) 828-833
    PubMedGoogle Scholar
  • 21 Magness RR, Sullivan JA, Li Y, Phernetton TM, Bird IM. Endothelial vasodilator production by uterine and systemic arteries. VI. Ovarian and pregnancy effects on eNOS and NO(x). Am J Physiol Heart Circ Physiol 2001; 280 (4) H1692-H1698
    PubMedGoogle Scholar
  • 22 Rupnow HL, Phernetton TM, Shaw CE, Modrick ML, Bird IM, Magness RR. Endothelial vasodilator production by uterine and systemic arteries. VII. Estrogen and progesterone effects on eNOS. Am J Physiol Heart Circ Physiol 2001; 280 (4) H1699-H1705
    PubMedGoogle Scholar
  • 23 Vagnoni KE, Shaw CE, Phernetton TM, Meglin BM, Bird IM, Magness RR. Endothelial vasodilator production by uterine and systemic arteries. III. Ovarian and estrogen effects on NO synthase. Am J Physiol 1998; 275 (5 Pt 2) H1845-H1856
    PubMedGoogle Scholar
  • 24 Magness RR, Rosenfeld CR, Hassan A, Shaul PW. Endothelial vasodilator production by uterine and systemic arteries. I. Effects of ANG II on PGI2 and NO in pregnancy. Am J Physiol 1996; 270 (6 Pt 2) H1914-H1923
    PubMedGoogle Scholar
  • 25 Salhab WA, Shaul PW, Cox BE, Rosenfeld CR. Regulation of types I and III NOS in ovine uterine arteries by daily and acute estrogen exposure. Am J Physiol Heart Circ Physiol 2000; 278 (6) H2134-H2142
    PubMedGoogle Scholar
  • 26 Liao WX, Magness RR, Chen DB. Expression of estrogen receptors-alpha and -beta in the pregnant ovine uterine artery endothelial cells in vivo and in vitro. Biol Reprod 2005; 72 (3) 530-537
    CrossrefPubMedGoogle Scholar
  • 27 Yi FX, Boeldt DS, Gifford SM , et al. Pregnancy enhances sustained Ca2+ bursts and endothelial nitric oxide synthase activation in ovine uterine artery endothelial cells through increased connexin 43 function. Biol Reprod 2010; 82 (1) 66-75
    CrossrefPubMedGoogle Scholar
  • 28 Magness RR, Rosenfeld CR. Local and systemic estradiol-17 beta: effects on uterine and systemic vasodilation. Am J Physiol 1989; 256 (4 Pt 1) E536-E542
    PubMedGoogle Scholar
  • 29 Rosenfeld CR, Roy T, Cox BE. Mechanisms modulating estrogen-induced uterine vasodilation. Vascul Pharmacol 2002; 38 (2) 115-125
    CrossrefPubMedGoogle Scholar
  • 30 Baker RS, Hirth J, Friedman A, Clark KE. ER alpha receptors mediate estrogen induced increases in uterine blood flow. J Soc Gynecol Investig 2003; 10 (Suppl 2) 332
    PubMedGoogle Scholar
  • 31 Mangelsdorf DJ, Thummel C, Beato M , et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83 (6) 835-839
    CrossrefPubMedGoogle Scholar
  • 32 Green S, Walter P, Kumar V , et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 1986; 320 (6058) 134-139
    CrossrefPubMedGoogle Scholar
  • 33 Greene GL, Gilna P, Waterfield M, Baker A, Hort Y, Shine J. Sequence and expression of human estrogen receptor complementary DNA. Science 1986; 231 (4742) 1150-1154
    CrossrefPubMedGoogle Scholar
  • 34 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 U S A 1996; 93 (12) 5925-5930
    CrossrefPubMedGoogle Scholar
  • 35 Byers MJ, Zangl A, Phernetton TM, Lopez G, Chen DB, Magness RR. Endothelial vasodilator production by ovine uterine and systemic arteries: ovarian steroid and pregnancy control of ERalpha and ERbeta levels. J Physiol 2005; 565 (Pt 1) 85-99
    CrossrefPubMedGoogle Scholar
  • 36 Fujimoto J, Hirose R, Sakaguchi H, Tamaya T. Clinical significance of expression of estrogen receptor alpha and beta mRNAs in ovarian cancers. Oncology 2000; 58 (4) 334-341
    CrossrefPubMedGoogle Scholar
  • 37 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 (2) 224-229
    CrossrefPubMedGoogle Scholar
  • 38 Giambiagi N, Pasqualini JR, Greene G, Jensen EV. Recognition of two forms of the estrogen receptor in the guinea-pig uterus at different stages of development by a monoclonal antibody to the human estrogen receptor. Dynamics of the translocation of these two forms to the nucleus. J Steroid Biochem 1984; 20 (1) 397-400
    CrossrefPubMedGoogle Scholar
  • 39 Batra S, Iosif S. Nuclear estrogen receptors in human uterine arteries. Gynecol Obstet Invest 1987; 24 (4) 250-255
    CrossrefPubMedGoogle Scholar
  • 40 Wu WX, Ma XH, Smith GC, Nathanielsz PW. Differential distribution of ERalpha and ERbeta mRNA in intrauterine tissues of the pregnant rhesus monkey. Am J Physiol Cell Physiol 2000; 278 (1) C190-C198
    PubMedGoogle Scholar
  • 41 Weihua Z, Saji S, Mäkinen S , et al. Estrogen receptor (ER) beta, a modulator of ERalpha in the uterus. Proc Natl Acad Sci U S A 2000; 97 (11) 5936-5941
    CrossrefPubMedGoogle Scholar
  • 42 Chang K, Zhang L. Review article: steroid hormones and uterine vascular adaptation to pregnancy. Reprod Sci 2008; 15 (4) 336-348
    CrossrefPubMedGoogle Scholar
    • 43 Malamas MS, Manas ES, McDevitt RE , et al. Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands. J Med Chem 2004; 47 (21) 5021-5040
      CrossrefPubMedGoogle Scholar
    • 44 Chambliss KL, Shaul PW. Rapid activation of endothelial NO synthase by estrogen: evidence for a steroid receptor fast-action complex (SRFC) in caveolae. Steroids 2002; 67 (6) 413-419
      CrossrefPubMedGoogle Scholar
    • 45 Rosenfeld CR, Morriss Jr FH, Battaglia FC, Makowski EL, Meschia G. Effect of estradiol-17beta on blood flow to reproductive and nonreproductive tissues in pregnant ewes. Am J Obstet Gynecol 1976; 124 (6) 618-629
      PubMedGoogle Scholar
    • 46 Kuiper GG, Carlsson B, Grandien K , et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997; 138 (3) 863-870
      CrossrefPubMedGoogle Scholar
    • 47 Taylor AH, Al-Azzawi F. Immunolocalisation of oestrogen receptor beta in human tissues. J Mol Endocrinol 2000; 24 (1) 145-155
      CrossrefPubMedGoogle Scholar
    • 48 Orimo A, Inoue S, Ikegami A , et al. Vascular smooth muscle cells as target for estrogen. Biochem Biophys Res Commun 1993; 195 (2) 730-736
      CrossrefPubMedGoogle Scholar
    • 49 Karas RH, Patterson BL, Mendelsohn ME. Human vascular smooth muscle cells contain functional estrogen receptor. Circulation 1994; 89 (5) 1943-1950
      CrossrefPubMedGoogle Scholar
    • 50 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 (4) 1501-1510
      CrossrefPubMedGoogle Scholar
    • 51 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 (4) 727-733
      CrossrefPubMedGoogle Scholar
    • 52 Kim-Schulze S, McGowan KA, Hubchak SC , et al. Expression of an estrogen receptor by human coronary artery and umbilical vein endothelial cells. Circulation 1996; 94 (6) 1402-1407
      CrossrefPubMedGoogle Scholar
    • 53 Caulin-Glaser T, Watson CA, Pardi R, Bender JR. Effects of 17beta-estradiol on cytokine-induced endothelial cell adhesion molecule expression. J Clin Invest 1996; 98 (1) 36-42
      CrossrefPubMedGoogle Scholar
    • 54 Hodges YK, Tung L, Yan XD, Graham JD, Horwitz KB, Horwitz LD. Estrogen receptors alpha and beta: prevalence of estrogen receptor beta mRNA in human vascular smooth muscle and transcriptional effects. Circulation 2000; 101 (15) 1792-1798
      CrossrefPubMedGoogle Scholar
    • 55 Andersson C, Lydrup ML, Fernö M, Idvall I, Gustafsson J, Nilsson BO. Immunocytochemical demonstration of oestrogen receptor beta in blood vessels of the female rat. J Endocrinol 2001; 169 (2) 241-247
      CrossrefPubMedGoogle Scholar
    • 56 Zhu Y, Bian Z, Lu P , et al. Abnormal vascular function and hypertension in mice deficient in estrogen receptor beta. Science 2002; 295 (5554) 505-508
      CrossrefPubMedGoogle Scholar
    • 57 Libby P, Bonow RO, Mann DL, Zipes DP . Pregnancy and cardiovascular disease. In: Libby P, Bonow RO, Mann DL, Zipes DP, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, PA: Saunders Elsevier; 2008. :1967
    • 58 Lang U, Baker RS, Braems GA, Clark KE. Inhibition of nitric oxide (NO) synthesis antagonises the oestrogen-induced increase in coronary blood. Eur J Cancer 2000; 36 (Suppl 4) 111
      PubMedGoogle Scholar
    • 59 Mershon JL, Baker RS, Clark KE. Estrogen increases iNOS expression in the ovine coronary artery. Am J Physiol Heart Circ Physiol 2002; 283 (3) H1169-H1180
      PubMedGoogle Scholar
    • 60 Magness RR, Shaw CE, Phernetton TM, Zheng J, Bird IM. Endothelial vasodilator production by uterine and systemic arteries. II. Pregnancy effects on NO synthase expression. Am J Physiol 1997; 272 (4 Pt 2) H1730-H1740
      PubMedGoogle Scholar
    • 61 Cárdenas H, Burke KA, Bigsby RM, Pope WF, Nephew KP. Estrogen receptor beta in the sheep ovary during the estrous cycle and early pregnancy. Biol Reprod 2001; 65 (1) 128-134
      CrossrefPubMedGoogle Scholar
    • 62 Hirata S, Shoda T, Kato J, Hoshi K. Isoform/variant mRNAs for sex steroid hormone receptors in humans. Trends Endocrinol Metab 2003; 14 (3) 124-129
      CrossrefPubMedGoogle Scholar
    • 63 Inoue S, Hoshino S, Miyoshi H , et al. Identification of a novel isoform of estrogen receptor, a potential inhibitor of estrogen action, in vascular smooth muscle cells. Biochem Biophys Res Commun 1996; 219 (3) 766-772
      CrossrefPubMedGoogle Scholar
    • 64 Kumar R, Johnson BH, Thompson EB. Overview of the structural basis for transcription regulation by nuclear hormone receptors. Essays Biochem 2004; 40: 27-39
      PubMedGoogle Scholar
    • 65 Kumar R, Thompson EB. The structure of the nuclear hormone receptors. Steroids 1999; 64 (5) 310-319
      CrossrefPubMedGoogle Scholar
    • 66 Gosden JR, Middleton PG, Rout D. Localization of the human oestrogen receptor gene to chromosome 6q24----q27 by in situ hybridization. Cytogenet Cell Genet 1986; 43 (3-4) 218-220
      CrossrefPubMedGoogle Scholar
    • 67 Krust A, Green S, Argos P , et al. The chicken oestrogen receptor sequence: homology with v-erbA and the human oestrogen and glucocorticoid receptors. EMBO J 1986; 5 (5) 891-897
      PubMedGoogle Scholar
    • 68 Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994; 22 (22) 4673-4680
      CrossrefPubMedGoogle Scholar
    • 69 Ascenzi P, Bocedi A, Marino M. Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Mol Aspects Med 2006; 27 (4) 299-402
      CrossrefPubMedGoogle Scholar
    • 70 Zhou W, Liu Z, Wu J , et al. Identification and characterization of two novel splicing isoforms of human estrogen-related receptor beta. J Clin Endocrinol Metab 2006; 91 (2) 569-579
      PubMedGoogle Scholar
    • 71 Kumar R, Thompson EB. Transactivation functions of the N-terminal domains of nuclear hormone receptors: protein folding and coactivator interactions. Mol Endocrinol 2003; 17 (1) 1-10
      CrossrefPubMedGoogle Scholar
    • 72 Katzenellenbogen JA, Muthyala R, Katzenellenbogen BS. Nature of the ligand-binding pocket of estrogen receptor alpha and beta: The search for subtype- selective ligands and implications for the prediction of estrogenic activity. Pure Appl Chem 2003; 75 (11–12) 2397-2403
      CrossrefPubMedGoogle Scholar
    • 73 DeLisle RK, Yu SJ, Nair AC, Welsh WJ. Homology modeling of the estrogen receptor subtype beta (ER-beta) and calculation of ligand binding affinities. J Mol Graph Model 2001; 20 (2) 155-167
      CrossrefPubMedGoogle Scholar
    • 74 Katzenellenbogen BS, Katzenellenbogen JA. Estrogen receptor transcription and transactivation: estrogen receptor alpha and estrogen receptor beta: regulation by selective estrogen receptor modulators and importance in breast cancer. Breast Cancer Res 2000; 2 (5) 335-344
      CrossrefPubMedGoogle Scholar
    • 75 Stauffer SR, Coletta CJ, Tedesco R , et al. Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists. J Med Chem 2000; 43 (26) 4934-4947
      CrossrefPubMedGoogle Scholar
    • 76 Compton DR, Sheng S, Carlson KE , et al. Pyrazolo[1,5-a]pyrimidines: estrogen receptor ligands possessing estrogen receptor beta antagonist activity. J Med Chem 2004; 47 (24) 5872-5893
      CrossrefPubMedGoogle Scholar
    • 77 Sun J, Huang YR, Harrington WR, Sheng S, Katzenellenbogen JA, Katzenellenbogen BS. Antagonists selective for estrogen receptor alpha. Endocrinology 2002; 143 (3) 941-947
      CrossrefPubMedGoogle Scholar
    • 78 Krom YD, Pires NM, Jukema JW , et al. Inhibition of neointima formation by local delivery of estrogen receptor alpha and beta specific agonists. Cardiovasc Res 2007; 73 (1) 217-226
      CrossrefPubMedGoogle Scholar
    • 79 Zhang HH, Feng L, Wang W, Magness RR, Chen DB. Estrogen-responsive nitroso-proteome in uterine artery endothelial cells: role of endothelial nitric oxide synthase and estrogen receptor-β. J Cell Physiol 2012; 227 (1) 146-159
      CrossrefPubMedGoogle Scholar
    • 80 van Hoorn WP. Identification of a second binding site in the estrogen receptor. J Med Chem 2002; 45 (3) 584-589
      CrossrefPubMedGoogle Scholar
    • 81 Wang L, Andersson S, Warner M, Gustafsson JA. Estrogen receptor (ER)beta knockout mice reveal a role for ERbeta in migration of cortical neurons in the developing brain. Proc Natl Acad Sci U S A 2003; 100 (2) 703-708
      CrossrefPubMedGoogle Scholar
    • 82 Rubanyi GM, Freay AD, Kauser K , et al. Vascular estrogen receptors and endothelium-derived nitric oxide production in the mouse aorta. Gender difference and effect of estrogen receptor gene disruption. J Clin Invest 1997; 99 (10) 2429-2437
      CrossrefPubMedGoogle Scholar
    • 83 Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M. Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 2000; 127 (19) 4277-4291
      PubMedGoogle Scholar
    • 84 Wang L, Andersson S, Warner M, Gustafsson JA. Estrogen receptor (ER)beta knockout mice reveal a role for ERbeta in migration of cortical neurons in the developing brain. Proc Natl Acad Sci U S A 2003; 100 (2) 703-708
      CrossrefPubMedGoogle Scholar
    • 85 Bilsel AS, Moini H, Tetik E, Aksungar F, Kaynak B, Ozer A. 17Beta-estradiol modulates endothelin-1 expression and release in human endothelial cells. Cardiovasc Res 2000; 46 (3) 579-584
      CrossrefPubMedGoogle Scholar
    • 86 Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T. Up-regulation of nitric oxide synthase by estradiol in human aortic endothelial cells. FEBS Lett 1995; 360 (3) 291-293
      CrossrefPubMedGoogle Scholar
    • 87 Kleinert H, Wallerath T, Euchenhofer C, Ihrig-Biedert I, Li H, Förstermann U. Estrogens increase transcription of the human endothelial NO synthase gene: analysis of the transcription factors involved. Hypertension 1998; 31 (2) 582-588
      CrossrefPubMedGoogle Scholar
    • 88 MacRitchie AN, Jun SS, Chen Z , et al. Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ Res 1997; 81 (3) 355-362
      CrossrefPubMedGoogle Scholar
    • 89 Weiner CP, Knowles RG, Moncada S. Induction of nitric oxide synthases early in pregnancy. Am J Obstet Gynecol 1994; 171 (3) 838-843
      PubMedGoogle Scholar
    • 90 Hayashi A, Kobayashi A, Takahashi R, Suzuki F, Nakagawa T, Kimotro K. Effects of voluntary running exercise on blood pressure and renin-angiotensin system in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. J Nutr Sci Vitaminol (Tokyo) 2000; 46 (4) 165-170
      CrossrefPubMedGoogle Scholar
    • 91 Mendelsohn C, Batourina E, Fung S, Gilbert T, Dodd J. Stromal cells mediate retinoid-dependent functions essential for renal development. Development 1999; 126 (6) 1139-1148
      PubMedGoogle Scholar
    • 92 Abbott CR, Rossi M, Kim M , et al. Investigation of the melanocyte stimulating hormones on food intake. Lack of evidence to support a role for the melanocortin-3-receptor. Brain Res 2000; 869 (1-2) 203-210
      CrossrefPubMedGoogle Scholar
    • 93 Sumi D, Ignarro LJ. Estrogen-related receptor alpha 1 up-regulates endothelial nitric oxide synthase expression. Proc Natl Acad Sci U S A 2003; 100 (24) 14451-14456
      CrossrefPubMedGoogle Scholar
    • 94 Furcht LT. Critical factors controlling angiogenesis: cell products, cell matrix, and growth factors. Lab Invest 1986; 55 (5) 505-509
      PubMedGoogle Scholar
    • 95 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 (3) 755-763
      CrossrefPubMedGoogle Scholar
    • 96 Jobe SO, Ramadoss J, Koch JM, Jiang Y, Zheng J, Magness RR. Estradiol-17beta and its cytochrome P450- and catechol-O-methyltransferase-derived metabolites stimulate proliferation in uterine artery endothelial cells: role of estrogen receptor-alpha versus estrogen receptor-beta. Hypertension 2010; 55 (4) 1005-1011
      CrossrefPubMedGoogle Scholar
    • 97 Oviedo PJ, Sobrino A, Laguna-Fernandez A , et al. Estradiol induces endothelial cell migration and proliferation through estrogen receptor-enhanced RhoA/ROCK pathway. Mol Cell Endocrinol 2011; 335 (2) 96-103
      CrossrefPubMedGoogle Scholar
    • 98 Critchley HO, Brenner RM, Henderson TA , et al. Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium. J Clin Endocrinol Metab 2001; 86 (3) 1370-1378
      CrossrefPubMedGoogle Scholar
    • 99 Matsubara K, Matsubara Y, King AG , et al. Regulation of endothelial cell proliferation by estrogen in reproductive organs. In: Kimura D, ed. Cell Growth Processes: New Research. Hauppauge, NY: : Nova Science Publishers Inc.; ; 2008: 159-182
      Google Scholar
    • 100 Cid MC, Schnaper HW, Kleinman HK. Estrogens and the vascular endothelium. Ann N Y Acad Sci 2002; 966: 143-157
      CrossrefPubMedGoogle Scholar
    • 101 Magness RR, Rosenfeld CR, Faucher DJ, Mitchell MD. Uterine prostaglandin production in ovine pregnancy: effects of angiotensin II and indomethacin. Am J Physiol 1992; 263 (1 Pt 2) H188-H197
      PubMedGoogle Scholar
    • 102 Naden RP, Iliya CA, Arant Jr BS, Gant Jr NF, Rosenfeld CR. Hemodynamic effects of indomethacin in chronically instrumented pregnant sheep. Am J Obstet Gynecol 1985; 151 (4) 484-494
      PubMedGoogle Scholar
    • 103 Klinge CM, Blankenship KA, Risinger KE , et al. Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. J Biol Chem 2005; 280 (9) 7460-7468
      PubMedGoogle Scholar
    • 104 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 (1 Pt 1) L119-L126
      PubMedGoogle Scholar
    • 105 Shaul PW, Smart EJ, Robinson LJ , et al. Acylation targets endothelial nitric-oxide synthase to plasmalemmal caveolae. J Biol Chem 1996; 271 (11) 6518-6522
      CrossrefPubMedGoogle Scholar
    • 106 Haynes MP, Sinha D, Russell KS , et al. Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ Res 2000; 87 (8) 677-682
      CrossrefPubMedGoogle Scholar
    • 107 Haynes MP, Li L, Sinha D , et al. Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen. J Biol Chem 2003; 278 (4) 2118-2123
      CrossrefPubMedGoogle Scholar
    • 108 Prabhakar P, Cheng V, Michel T. A chimeric transmembrane domain directs endothelial nitric-oxide synthase palmitoylation and targeting to plasmalemmal caveolae. J Biol Chem 2000; 275 (25) 19416-19421
      CrossrefPubMedGoogle Scholar
    • 109 Shaul PW, Anderson RG. Role of plasmalemmal caveolae in signal transduction. Am J Physiol 1998; 275 (5 Pt 1) L843-L851
      PubMedGoogle Scholar
    • 110 Chen D, Zangl AL, Zhao Q , et al. Ovine caveolin-1: cDNA cloning, E. coli expression, and association with endothelial nitric oxide synthase. Mol Cell Endocrinol 2001; 175 (1-2) 41-56
      CrossrefPubMedGoogle Scholar
    • 111 Bird IM, Zhang L, Magness RR. Possible mechanisms underlying pregnancy-induced changes in uterine artery endothelial function. Am J Physiol Regul Integr Comp Physiol 2003; 284 (2) R245-R258
      PubMedGoogle Scholar
    • 112 Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev 2002; 23 (5) 665-686
      CrossrefPubMedGoogle Scholar
    • 113 Chambliss KL, Yuhanna IS, Anderson RG, Mendelsohn ME, Shaul PW. ERbeta has nongenomic action in caveolae. Mol Endocrinol 2002; 16 (5) 938-946
      CrossrefPubMedGoogle Scholar
    • 114 Zhang HH, Feng L, Livnat I , et al. Estradiol-17beta stimulates specific receptor and endogenous nitric oxide-dependent dynamic endothelial protein S-nitrosylation: analysis of endothelial nitrosyl-proteome. Endocrinology 2010; 151 (8) 3874-3887
      CrossrefPubMedGoogle Scholar
    • 115 Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 1999; 103 (3) 401-406
      CrossrefPubMedGoogle Scholar
    • 116 Wu Q, Chambliss K, Umetani M, Mineo C, Shaul PW. Non-nuclear estrogen receptor signaling in the endothelium. J Biol Chem 2011; 286 (17) 14737-14743
      CrossrefPubMedGoogle Scholar
    • 117 Song RX, Barnes CJ, Zhang Z, Bao Y, Kumar R, Santen RJ. The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor alpha to the plasma membrane. Proc Natl Acad Sci U S A 2004; 101 (7) 2076-2081
      CrossrefPubMedGoogle Scholar
    • 118 Pedram A, Razandi M, Sainson RC, Kim JK, Hughes CC, Levin ER. A conserved mechanism for steroid receptor translocation to the plasma membrane. J Biol Chem 2007; 282 (31) 22278-22288
      CrossrefPubMedGoogle Scholar
    • 119 Acconcia F, Ascenzi P, Bocedi A , et al. Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol. Mol Biol Cell 2005; 16 (1) 231-237
      PubMedGoogle Scholar
    • 120 Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M. S-palmitoylation modulates human estrogen receptor-alpha functions. Biochem Biophys Res Commun 2004; 316 (3) 878-883
      CrossrefPubMedGoogle Scholar
    • 121 Razandi M, Pedram A, Levin ER. Heat shock protein 27 is required for sex steroid receptor trafficking to and functioning at the plasma membrane. Mol Cell Biol 2010; 30 (13) 3249-3261
      CrossrefPubMedGoogle Scholar
    • 122 Mount PF, Kemp BE, Power DA. Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol 2007; 42 (2) 271-279
      CrossrefPubMedGoogle Scholar
    • 123 Boo YC, Hwang J, Sykes M , et al. Shear stress stimulates phosphorylation of eNOS at Ser(635) by a protein kinase A-dependent mechanism. Am J Physiol Heart Circ Physiol 2002; 283 (5) H1819-H1828
      PubMedGoogle Scholar
    • 124 Michell BJ, Griffiths JE, Mitchelhill KI , et al. The Akt kinase signals directly to endothelial nitric oxide synthase. Curr Biol 1999; 9 (15) 845-848
      CrossrefPubMedGoogle Scholar
    • 125 Scobie GA, Macpherson S, Millar MR, Groome NP, Romana PG, Saunders PT. Human oestrogen receptors: differential expression of ER alpha and beta and the identification of ER beta variants. Steroids 2002; 67 (12) 985-992
      CrossrefPubMedGoogle Scholar
    • 126 Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res 1991; 51 (15) 3867-3873
      PubMedGoogle Scholar
    • 127 Wakeling AE, Valcaccia B, Newboult E, Green LR. Non-steroidal antioestrogens—receptor binding and biological response in rat uterus, rat mammary carcinoma and human breast cancer cells. J Steroid Biochem 1984; 20 (1) 111-120
      CrossrefPubMedGoogle Scholar
    • 128 Walter G, Liebl R, von Angerer E. Synthesis and biological evaluation of stilbene-based pure estrogen antagonists. Bioorg Med Chem Lett 2004; 14 (18) 4659-4663
      CrossrefPubMedGoogle Scholar
    • 129 Kraichely DM, Sun J, Katzenellenbogen JA, Katzenellenbogen BS. Conformational changes and coactivator recruitment by novel ligands for estrogen receptor-alpha and estrogen receptor-beta: correlations with biological character and distinct differences among SRC coactivator family members. Endocrinology 2000; 141 (10) 3534-3545
      CrossrefPubMedGoogle Scholar
    • 130 Yang C, Xu G, Li J , et al. Benzothiophenes containing a piperazine side chain as selective ligands for the estrogen receptor alpha and their bioactivities in vivo. Bioorg Med Chem Lett 2005; 15 (5) 1505-1507
      CrossrefPubMedGoogle Scholar
    • 131 Sun J, Meyers MJ, Fink BE, Rajendran R, Katzenellenbogen JA, Katzenellenbogen BS. Novel ligands that function as selective estrogens or antiestrogens for estrogen receptor-alpha or estrogen receptor-beta. Endocrinology 1999; 140 (2) 800-804
      CrossrefPubMedGoogle Scholar
    • 132 Minutolo F, Bertini S, Granchi C , et al. Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta. J Med Chem 2009; 52 (3) 858-867
      CrossrefPubMedGoogle Scholar
    • 133 Fang X, Wong S, Mitchell BF. Effects of RU486 on estrogen, progesterone, oxytocin, and their receptors in the rat uterus during late gestation. Endocrinology 1997; 138 (7) 2763-2768
      CrossrefPubMedGoogle Scholar