Gender Medicine: The Journal for the Study of Sex & Gender Differences
Volume 8, Issue 6 , Pages 343-354 , December 2011

Evidence That the G Protein–Coupled Membrane Receptor GPR30 Contributes to the Cardiovascular Actions of Estrogen

  • Sarah H. Lindsey, PhD

      Affiliations

    • Corresponding Author InformationAddress correspondence to: Sarah H. Lindsey, PhD, Hypertension and Vascular Research Center, Wake Forest School of Medicine, Hanes Building, 6th Floor, Medical Center Boulevard, Winston-Salem, NC 27157-1032
  • ,
  • Mark C. Chappell, PhD, FAHA

,Accepted 26 October 2011.

References 

  1. Roger VL , Go AS , Lloyd-Jones DM , et al.  Heart disease and stroke statistics—2011 update: a report from the American Heart Association . Circulation . 2011;123:e18–e209
  2. Rossouw JE , Anderson GL , Prentice RL , et al.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial . JAMA . 2002;288:321–333
  3. Anderson GL , Limacher M , Assaf AR , et al.  Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled Trial . JAMA . 2004;291:1701–1712
  4. Pietras RJ , Szego CM . Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells . Nature . 1977;265:69–72
  5. Wang Z , Zhang X , Shen P , et al.  Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66 . Biochem Biophys Res Commun . 2005;336:1023–1027
  6. Carmeci C , Thompson DA , Ring HZ , et al.  Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer . Genomics . 1997;45:607–617
  7. Wang D , Hu L , Zhang G , et al.  G protein-coupled receptor 30 in tumor development . Endocrine . 2010;38:29–37
  8. Chappell MC , Gallagher PE , Averill DB , et al.  Estrogen or the AT1 antagonist olmesartan reverses the development of profound hypertension in the congenic mRen(2).Lewis rat . Hypertension . 2003;42:781–786
  9. Crofton JT , Share L . Gonadal hormones modulate deoxycorticosterone-salt hypertension in male and female rats . Hypertension . 1997;29:494–499
  10. Harrison-Bernard LM , Schulman IH , Raij L . Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity . Hypertension . 2003;42:1157–1163
  11. Brosnihan KB , Moriguchi A , Nakamoto H , et al.  Estrogen augments the contribution of nitric oxide to blood pressure regulation in transgenic hypertensive rats expressing the mouse Ren-2 gene . Am J Hypertens . 1994;7:576–582
  12. Pendergrass KD , Westwood BM , Chappell MC . Differential expression of neprilysin and angiotensin-converting enzyme 2 may contribute to the gender disparity in the hypertensive mRen2.Lewis strain . Hypertension . 2007;50:e75–e155
  13. Chappell MC , Yamaleyeva LM , Westwood BM . Estrogen and salt sensitivity in the female mRen(2).Lewis rat . Am J Physiol Regul Integr Comp Physiol . 2006;291:R1557–R1563
  14. Chappell MC . Emerging evidence for a functional angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS receptor axis: more than regulation of blood pressure? . Hypertension . 2007;50:596–599
  15. Lindsey SH , Cohen JA , Brosnihan KB , et al.  Chronic treatment with the G protein-coupled receptor 30 agonist G-1 decreases blood pressure in ovariectomized mRen2.Lewis rats . Endocrinology . 2009;150:3753–3758
  16. Pines A , Fisman EZ , Drory Y , et al.  The effects of sublingual estradiol on left ventricular function at rest and exercise in postmenopausal women: an echocardiographic assessment . Menopause . 1998;5:79–85
  17. Leonardo F , Medeirus C , Rosano GM , et al.  Effect of acute administration of estradiol 17 beta on aortic blood flow in menopausal women . Am J Cardiol . 1997;80:791–793
  18. Perera M , Petrie JR , Hillier C , et al.  Hormone replacement therapy can augment vascular relaxation in post-menopausal women with type 2 diabetes . Hum Reprod . 2002;17:497–502
  19. Cruz MN , Douglas G , Gustafsson JA , et al.  Dilatory responses to estrogenic compounds in small femoral arteries of male and female estrogen receptor-beta knockout mice . Am J Physiol Heart Circ Physiol . 2006;290:H823–H829
  20. 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;99:2429–2437
  21. Lindsey SH , Carver KA , Prossnitz ER , Chappell MC . Vasodilation in response to the GPR30 agonist G-1 is not different from estradiol in the mRen2.Lewis female rat . J Cardiovasc Pharmacol . 2011;57:598–603
  22. Nilsson BO , Ekblad E , Heine T , Gustafsson JA . Increased magnitude of relaxation to oestrogen in aorta from oestrogen receptor beta knock-out mice . J Endocrinol . 2000;166:R5–R9
  23. Iafrati MD , Karas RH , Aronovitz M , et al.  Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice . Nat Med . 1997;3:545–548
  24. Karas RH , Hodgin JB , Kwoun M , et al.  Estrogen inhibits the vascular injury response in estrogen receptor beta-deficient female mice . Proc Natl Acad Sci U S A . 1999;96:15133–15136
  25. Ogata R , Inoue Y , Nakano H , et al.  Oestradiol-induced relaxation of rabbit basilar artery by inhibition of voltage-dependent Ca channels through GTP-binding protein . Br J Pharmacol . 1996;117:351–359
  26. Kitazawa T , Hamada E , Kitazawa K , Gaznabi AK . Non-genomic mechanism of 17 beta-oestradiol-induced inhibition of contraction in mammalian vascular smooth muscle . J Physiol . 1997;499(pt 2):497–511
  27. Haas E , Meyer MR , Schurr U , et al.  Differential effects of 17beta-estradiol on function and expression of estrogen receptor alpha, estrogen receptor beta, and GPR30 in arteries and veins of patients with atherosclerosis . Hypertension . 2007;49:1358–1363
  28. Martensson UE , Salehi SA , Windahl S , et al.  Deletion of the G protein-coupled receptor GPR30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice . Endocrinology . 2008;150:687–698
  29. Haas E , Bhattacharya I , Brailoiu E , et al.  Regulatory role of G protein-coupled estrogen receptor for vascular function and obesity . Circ Res . 2009;104:288–291
  30. Broughton BR , Miller AA , Sobey CG . Endothelium-dependent relaxation by G protein-coupled receptor 30 agonists in rat carotid arteries . Am J Physiol Heart Circ Physiol . 2010;298:H1055–H1061
  31. Meyer MR , Baretella O , Prossnitz ER , Barton M . Dilation of epicardial coronary arteries by the G protein-coupled estrogen receptor agonists G-1 and ICI 182,780 . Pharmacology . 2010;86:58–64
  32. Ding Q , Gros R , Limbird LE , et al.  Estradiol-mediated ERK phosphorylation and apoptosis in vascular smooth muscle cells requires GPR 30 . Am J Physiol Cell Physiol . 2009;297:C1178–C1187
  33. Gros R , Ding Q , Sklar LA , et al.  GPR30 expression is required for the mineralocorticoid receptor-independent rapid vascular effects of aldosterone . Hypertension . 2011;57:442–451
  34. Ma Y , Qiao X , Falone AE , et al.  Gender-specific reduction in contraction is associated with increased estrogen receptor expression in single vascular smooth muscle cells of female rat . Cell Physiol Biochem . 2010;26:457–470
  35. Lindsey SH , Yamaleyeva LM , Brosnihan KB , et al.  Estrogen receptor GPR30 reduces oxidative stress and proteinuria in the salt-sensitive female mRen2.Lewis rat . Hypertension . 2011;58:665–671
  36. Ho KK , Anderson KM , Kannel WB , et al.  Survival after the onset of congestive heart failure in Framingham Heart Study subjects . Circulation . 1993;88:107–115
  37. Masoudi FA , Havranek EP , Smith G , et al.  Gender, age, and heart failure with preserved left ventricular systolic function . J Am Coll Cardiol . 2003;41:217–223
  38. Sites CK , Tischler MD , Blackman JA , et al.  Effect of short-term hormone replacement therapy on left ventricular mass and contractile function . Fertil Steril . 1999;71:137–143
  39. Groban L , Yamaleyeva LM , Westwood BM , et al.  Progressive diastolic dysfunction in the female mRen(2) (Lewis rat: influence of salt and ovarian hormones) . J Gerontol A Biol Sci Med Sci . 2008;63:3–11
  40. Brower GL , Gardner JD , Janicki JS . Gender mediated cardiac protection from adverse ventricular remodeling is abolished by ovariectomy . Mol Cell Biochem . 2003;251:89–95
  41. Kolodgie FD , Farb A , Litovsky SH , et al.  Myocardial protection of contractile function after global ischemia by physiologic estrogen replacement in the ovariectomized rat . J Mol Cell Cardiol . 1997;29:2403–2414
  42. Cavasin MA , Sankey SS , Yu AL , et al.  Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction . Am J Physiol Heart Circ Physiol . 2003;284:H1560–H1569
  43. Patten RD , Pourati I , Aronovitz MJ , et al.  17Beta-estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling . Circ Res . 2004;95:692–699
  44. Dubey RK , Gillespie DG , Jackson EK , Keller PJ . 17Beta-estradiol, its metabolites, and progesterone inhibit cardiac fibroblast growth . Hypertension . 1998;31:522–528
  45. Deschamps AM , Murphy E . Activation of a novel estrogen receptor, GPER, is cardioprotective in male and female rats . Am J Physiol Heart Circ Physiol . 2009;297:H1806–H1813
  46. Filice E , Recchia AG , Pellegrino D , et al.  A new membrane G protein-coupled receptor (GPR30) is involved in the cardiac effects of 17beta-estradiol in the male rat . J Physiol Pharmacol . 2009;60:3–10
  47. Patel VH , Chen J , Ramanjaneya M , et al.  G-protein coupled estrogen receptor 1 expression in rat and human heart: protective role during ischaemic stress . Int J Mol Med . 2010;26:193–199
  48. Weil BR , Manukyan MC , Herrmann JL , et al.  Signaling Via GPR30 protects the myocardium from ischemia/reperfusion injury . Surgery . 2010;148:436–443
  49. Bopassa JC , Eghbali M , Toro L , Stefani E . A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury . Am J Physiol Heart Circ Physiol . 2010;298:H16–H23
  50. Recchia AG , De Francesco EM , Vivacqua A , et al.  The G protein-coupled receptor 30 is up-regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) in breast cancer cells and cardiomyocytes . J Biol Chem . 2011;286:10773–10782
  51. Jessup JA , Lindsey SH , Wang H , et al.  Attenuation of salt-induced cardiac remodeling and diastolic dysfunction by the GPER agonist G-1 in female mRen2.Lewis rats . PLoS One . 2010;5:e15433
  52. Delbeck M , Golz S , Vonk R , et al.  Impaired left-ventricular cardiac function in male GPR30-deficient mice . Mol Med Report . 2011;4:37–40
  53. Booth EA , Obeid NR , Lucchesi BR . Activation of estrogen receptor-alpha protects the in vivo rabbit heart from ischemia-reperfusion injury . Am J Physiol Heart Circ Physiol . 2005;289:H2039–H2047
  54. Fliegner D , Schubert C , Penkalla A , et al.  Female sex and estrogen receptor-beta attenuate cardiac remodeling and apoptosis in pressure overload . Am J Physiol Regul Integr Comp Physiol . 2010;298:R1597–R1606
  55. Skavdahl M , Steenbergen C , Clark J , et al.  Estrogen receptor-beta mediates male-female differences in the development of pressure overload hypertrophy . Am J Physiol Heart Circ Physiol . 2005;288:H469–H476
  56. Yamori Y , Liu L , Ikeda K , et al.  Different associations of blood pressure with 24-hour urinary sodium excretion among pre- and post-menopausal women (WHO Cardiovascular Diseases and Alimentary Comparison (WHO-CARDIAC) Study) . J Hypertens . 2001;19:535–538
  57. Schulman IH , Aranda P , Raij L , et al.  Surgical menopause increases salt sensitivity of blood pressure . Hypertension . 2006;47:1168–1174
  58. Scuteri A , Lakatta EG , Anderson DE , Fleg JL . Transdermal 17 beta-oestradiol reduces salt sensitivity of blood pressure in postmenopausal women . J Hypertens . 2003;21:2419–2420
  59. Cohen JA , Lindsey SH , Pirro NT , et al.  Influence of estrogen depletion and salt loading on renal angiotensinogen expression in the mRen(2) (Lewis strain) . Am J Physiol Renal Physiol . 2010;299:F35–F42
  60. Zheng W , Ji H , Maric C , et al.  Effect of dietary sodium on estrogen regulation of blood pressure in Dahl salt-sensitive rats . Am J Physiol Heart Circ Physiol . 2008;294:H1508–H1513
  61. Mankhey RW , Bhatti F , Maric C . 17Beta-estradiol replacement improves renal function and pathology associated with diabetic nephropathy . Am J Physiol Renal Physiol . 2005;288:F399–F405
  62. Hutchens MP , Nakano T , Kosaka Y , et al.  Estrogen is renoprotective via a nonreceptor-dependent mechanism after cardiac arrest in vivo . Anesthesiology . 2010;112:395–405
  63. Ji H , Menini S , Mok K , et al.  Gonadal steroid regulation of renal injury in renal wrap hypertension . Am J Physiol Renal Physiol . 2005;288:F513–F520
  64. Hazell GG , Yao ST , Roper JA , et al.  Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues . J Endocrinol . 2009;202:223–236
  65. Cheng SB , Graeber CT , Quinn JA , Filardo EJ . Retrograde transport of the transmembrane estrogen receptor, G-protein-coupled-receptor-30 (GPR30/GPER) from the plasma membrane towards the nucleus . Steroids . 2011;76:892–896
  66. Christou DD , Jones PP , Jordan J , et al.  Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than men . Circulation . 2005;111:494–498
  67. Hirshoren N , Tzoran I , Makrienko I , et al.  Menstrual cycle effects on the neurohumoral and autonomic nervous systems regulating the cardiovascular system . J Clin Endocrinol Metab . 2002;87:1569–1575
  68. Minson CT , Halliwill JR , Young TM , Joyner MJ . Influence of the menstrual cycle on sympathetic activity, baroreflex sensitivity, and vascular transduction in young women . Circulation . 2000;101:862–868
  69. Goldman RK , Azar AS , Mulvaney JM , et al.  Baroreflex sensitivity varies during the rat estrous cycle: role of gonadal steroids . Am J Physiol Regul Integr Comp Physiol . 2009;296:R1419–R1426
  70. Saleh MC , Connell BJ , Saleh TM . Autonomic and cardiovascular reflex responses to central estrogen injection in ovariectomized female rats . Brain Res . 2000;879:105–114
  71. Xue B , Zhao Y , Johnson AK , Hay M . Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species . Am J Physiol Heart Circ Physiol . 2008;295:H1025–H1032
  72. Brailoiu E , Dun SL , Brailoiu GC , et al.  Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system . J Endocrinol . 2007;193:311–321
  73. Dun SL , Brailoiu GC , Gao X , et al.  Expression of estrogen receptor GPR30 in the rat spinal cord and in autonomic and sensory ganglia . J Neurosci Res . 2009;87:1610–1619
  74. Spary EJ , Maqbool A , Batten TF . Oestrogen receptors in the central nervous system and evidence for their role in the control of cardiovascular function . J Chem Neuroanat . 2009;38:185–196
  75. Qiao GF , Li BY , Lu YJ , et al.  17Beta-estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats . Am J Physiol Cell Physiol . 2009;297:C654–C664
  76. Schunkert H , Danser AH , Hense HW , et al.  Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women . Circulation . 1997;95:39–45
  77. Brosnihan KB , Weddle D , Anthony MS , et al.  Effects of chronic hormone replacement on the renin-angiotensin system in cynomolgus monkeys . J Hypertens . 1997;15:719–726
  78. Klett C , Ganten D , Hellmann W , et al.  Regulation of hepatic angiotensinogen synthesis and secretion by steroid hormones . Endocrinology . 1992;130:3660–3668
  79. Gallagher PE , Li P , Lenhart JR , et al.  Estrogen regulation of angiotensin-converting enzyme MRNA . Hypertension . 1999;33:323–328
  80. Nickenig G , Baumer AT , Grohe C , et al.  Estrogen modulates AT1 receptor gene expression in vitro and in vivo . Circulation . 1998;97:2197–2201
  81. Brosnihan KB , Hodgin JB , Smithies O , et al.  Tissue-specific regulation of ACE/ACE2 and AT1/AT2 receptor gene expression by oestrogen in apolipoprotein E/oestrogen receptor-alpha knock-out mice . Exp Physiol . 2008;93:658–664
  82. Allred AJ , Diz DI , Ferrario CM , Chappell MC . Pathways for angiotensin-(1-7) metabolism in pulmonary and renal tissues . Am J Physiol Renal Physiol . 2000;279:F841–F850
  83. Yamada K , Iyer SN , Chappell MC , et al.  Converting enzyme determines plasma clearance of angiotensin-(1-7) . Hypertension . 1998;32:496–502
  84. Ji H , Menini S , Zheng W , et al.  Role of angiotensin-converting enzyme 2 and angiotensin(1-7) in 17beta-oestradiol regulation of renal pathology in renal wrap hypertension in rats . Exp Physiol . 2008;93:648–657
  85. Muller C , Shewale S , Gurley SB , et al.   Sex and species differences in ACE, ACE2 and neprilysin of the renal brush border . Hypertension . 2011;58:e153
  86. Shimada K , Kitazato KT , Kinouchi T , et al.  Activation of estrogen receptor-alpha and of angiotensin-converting enzyme 2 suppresses ischemic brain damage in oophorectomized rats . Hypertension . 2011;57:1161–1166

PII: S1550-8579(11)00223-3

doi: 10.1016/j.genm.2011.10.004

Gender Medicine: The Journal for the Study of Sex & Gender Differences
Volume 8, Issue 6 , Pages 343-354 , December 2011