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Estrogen-mediated mechanisms in hypertension and other cardiovascular diseases

Abstract

Cardiovascular disease (CVD) is the leading cause of death globally for men and women. Premenopausal women have a lower incidence of hypertension and other cardiovascular events than men of the same age, but diminished sex differences after menopause implicates 17-beta-estradiol (E2) as a protective agent. The cardioprotective effects of E2 are mediated by nuclear estrogen receptors (ERα and ERβ) and a G protein-coupled estrogen receptor (GPER). This review summarizes both established as well as emerging estrogen-mediated mechanisms that underlie sex differences in the vasculature during hypertension and CVD. In addition, remaining knowledge gaps inherent in the association of sex differences and E2 are identified, which may guide future clinical trials and experimental studies in this field.

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Fig. 1: The protective cardiovascular actions of estrogen are mediated by nuclear receptors ERα and ERβ as well as the membrane G protein-coupled estrogen receptor (GPER).

References

  1. Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, et al. Heart disease and stroke statistics-2022 update: a report from the American Heart Association. Circulation. 2022;145:e153–e639.

    Article  PubMed  Google Scholar 

  2. Tepper PG, Randolph JF Jr., McConnell DS, Crawford SL, El Khoudary SR, Joffe H, et al. Trajectory clustering of estradiol and follicle-stimulating hormone during the menopausal transition among women in the Study of Women’s Health across the Nation (SWAN). J Clin Endocrinol Metab. 2012;97:2872–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Liu Y, Ding J, Bush TL, Longenecker JC, Nieto FJ, Golden SH, et al. Relative androgen excess and increased cardiovascular risk after menopause: a hypothesized relation. Am J Epidemiol. 2001;154:489–94.

    Article  PubMed  CAS  Google Scholar 

  4. Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas. 1995;21:103–13.

    Article  PubMed  CAS  Google Scholar 

  5. Wang N, Shao H, Chen Y, Xia F, Chi C, Li Q, et al. Follicle-stimulating hormone, its association with cardiometabolic risk factors, and 10-year risk of cardiovascular disease in postmenopausal women. J Am Heart Assoc. 2017;6:e005918.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Jackson EA, El Khoudary SR, Crawford SL, Matthews K, Joffe H, Chae C, et al. Hot flash frequency and blood pressure: data from the study of women’s health across the nation. J Women’s Health. 2016;25:1204–9.

    Article  Google Scholar 

  7. Samargandy S, Matthews KA, Brooks MM, Barinas-Mitchell E, Magnani JW, Thurston RC, et al. Trajectories of blood pressure in midlife women: does menopause matter? Circ Res. 2022;130:312–22.

    Article  PubMed  CAS  Google Scholar 

  8. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, 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;288:321–33.

    Article  PubMed  CAS  Google Scholar 

  9. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–77.

    Article  PubMed  CAS  Google Scholar 

  10. Chappell MC, Yamaleyeva LM, Westwood BM. Estrogen and salt sensitivity in the female mRen(2). Lewis rat. Am J Physiol Regulatory, Integr Comp Physiol. 2006;291:R1557–63.

    Article  CAS  Google Scholar 

  11. Zhao Z, Wang H, Jessup JA, Lindsey SH, Chappell MC, Groban L. Role of estrogen in diastolic dysfunction. Am J Physiol Heart Circ Physiol. 2014;306:H628–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Oparil S, Chen SJ, Chen YF, Durand JN, Allen L, Thompson JA. Estrogen attenuates the adventitial contribution to neointima formation in injured rat carotid arteries. Cardiovas Res. 1999;44:608–14.

    Article  CAS  Google Scholar 

  13. Wang Z, Li X, Zhang D. Impact of hysterectomy on cardiovascular disease and different subtypes: a meta-analysis. Arch Gynecol Obstet. 2022;305:1255–63.

    Article  PubMed  Google Scholar 

  14. Ingelsson E, Lundholm C, Johansson AL, Altman D. Hysterectomy and risk of cardiovascular disease: a population-based cohort study. Eur Heart J. 2011;32:745–50.

    Article  PubMed  Google Scholar 

  15. Howard BV, Kuller L, Langer R, Manson JE, Allen C, Assaf A, et al. Risk of cardiovascular disease by hysterectomy status, with and without oophorectomy: the Women’s Health Initiative Observational Study. Circulation. 2005;111:1462–70.

    Article  PubMed  Google Scholar 

  16. Simpson E, Santen RJ. Celebrating 75 years of oestradiol. J Mol Endocrinol. 2015;55:T1–20.

    Article  PubMed  CAS  Google Scholar 

  17. Jensen EV, Desombre ER, Kawashima T, Suzuki T, Kyser K, Jungblut PW. Estrogen-binding substances of target tissues. Science. 1967;158:529–30.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Klein-Hitpass L, Schorpp M, Wagner U, Ryffel GU. An estrogen-responsive element derived from the 5’ flanking region of the Xenopus vitellogenin A2 gene functions in transfected human cells. Cell. 1986;46:1053–61.

    Article  PubMed  CAS  Google Scholar 

  20. Tee MK, Rogatsky I, Tzagarakis-Foster C, Cvoro A, An J, Christy RJ, et al. Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004;15:1262–72.

    Article  PubMed  CAS  Google Scholar 

  21. Gurrala R, Kilanowski-Doroh IM, Hutson DD, Ogola BO, Zimmerman MA, Katakam PVG, et al. Alterations in the estrogen receptor profile of cardiovascular tissues during aging. GeroScience. 2021;43:433–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Hutson DD, Gurrala R, Ogola BO, Zimmerman MA, Mostany R, Satou R, et al. Estrogen receptor profiles across tissues from male and female Rattus norvegicus. Biol Sex Differ. 2019;10:4.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Pugach EK, Blenck CL, Dragavon JM, Langer SJ, Leinwand LA. Estrogen receptor profiling and activity in cardiac myocytes. Mol Cell Endocrinol. 2016;431:62–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Ropero AB, Eghbali M, Minosyan TY, Tang G, Toro L, Stefani E. Heart estrogen receptor alpha: distinct membrane and nuclear distribution patterns and regulation by estrogen. J Mol Cell Cardiol. 2006;41:496–510.

    Article  PubMed  CAS  Google Scholar 

  25. Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M, et al. Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ Res. 2000;87:677–82.

    Article  PubMed  CAS  Google Scholar 

  26. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005;307:1625–30.

    Article  PubMed  CAS  Google Scholar 

  27. Chung TH, Wang SM, Liang JY, Yang SH, Wu JC. The interaction of estrogen receptor alpha and caveolin-3 regulates connexin43 phosphorylation in metabolic inhibition-treated rat cardiomyocytes. Int J Biochem Cell Biol. 2009;41:2323–33.

    Article  PubMed  CAS  Google Scholar 

  28. Chambliss KL, Yuhanna IS, Mineo C, Liu P, German Z, Sherman TS, et al. Estrogen receptor alpha and endothelial nitric oxide synthase are organized into a functional signaling module in caveolae. Circ Res. 2000;87:E44–52.

    Article  PubMed  CAS  Google Scholar 

  29. Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev. 1999;20:358–417.

    Article  PubMed  CAS  Google Scholar 

  30. Mendelsohn ME. Genomic and nongenomic effects of estrogen in the vasculature. Am J Cardiol. 2002;90:3F–6F.

    Article  PubMed  CAS  Google Scholar 

  31. 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;101:1792–8.

    Article  PubMed  CAS  Google Scholar 

  32. Somani YB, Pawelczyk JA, De Souza MJ, Kris-Etherton PM, Proctor DN. Aging women and their endothelium: probing the relative role of estrogen on vasodilator function. Am J Physiol Heart Circ Physiol. 2019;317:H395–H404.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Khalil RA. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease. Biochem Pharmacol. 2013;86:1627–42.

    Article  PubMed  CAS  Google Scholar 

  34. Murphy E. Estrogen signaling and cardiovascular disease. Circ Res. 2011;109:687–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Guivarc’h E, Favre J, Guihot AL, Vessieres E, Grimaud L, Proux C, et al. Nuclear activation function 2 estrogen receptor alpha attenuates arterial and renal alterations due to aging and hypertension in female mice. J Am Heart Assoc. 2020;9:e013895.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Pinna C, Cignarella A, Sanvito P, Pelosi V, Bolego C. Prolonged ovarian hormone deprivation impairs the protective vascular actions of estrogen receptor alpha agonists. Hypertension. 2008;51:1210–7.

    Article  PubMed  CAS  Google Scholar 

  37. Connelly PJ, Casey H, Montezano AC, Touyz RM, Delles C. Sex steroids receptors, hypertension, and vascular ageing. J Hum Hypertens. 2022;36:120–5.

    Article  PubMed  Google Scholar 

  38. Widder J, Pelzer T, von Poser-Klein C, Hu K, Jazbutyte V, Fritzemeier KH, et al. Improvement of endothelial dysfunction by selective estrogen receptor-alpha stimulation in ovariectomized SHR. Hypertension. 2003;42:991–6.

    Article  PubMed  CAS  Google Scholar 

  39. Xue B, Pamidimukkala J, Lubahn DB, Hay M. Estrogen receptor-alpha mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice. Am J Physiol Heart Circ Physiol. 2007;292:H1770–6.

    Article  PubMed  CAS  Google Scholar 

  40. Irsik DL, Carmines PK, Lane PH. Classical estrogen receptors and ERalpha splice variants in the mouse. PloS one. 2013;8:e70926.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Aryan L, Younessi D, Zargari M, Banerjee S, Agopian J, Rahman S, et al. The role of estrogen receptors in cardiovascular disease. Int J Mol Sci. 2020;21:4314.

    Article  PubMed Central  CAS  Google Scholar 

  42. Arao Y, Gruzdev A, Scott GJ, Ray MK, Donoghue LJ, Neufeld TI, et al. A novel mouse model to analyze non-genomic ERα physiological actions. J Endocr Soc. 2022;6:1–11.

    Article  Google Scholar 

  43. Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, et al. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006;114:1829–37.

    Article  PubMed  CAS  Google Scholar 

  44. Jankowska EA, Rozentryt P, Ponikowska B, Hartmann O, Kustrzycka-Kratochwil D, Reczuch K, et al. Circulating estradiol and mortality in men with systolic chronic heart failure. JAMA. 2009;301:1892–901.

    Article  PubMed  CAS  Google Scholar 

  45. Yeap BB, Hyde Z, Almeida OP, Norman PE, Chubb SA, Jamrozik K, et al. Lower testosterone levels predict incident stroke and transient ischemic attack in older men. J Clin Endocrinol Metab. 2009;94:2353–9.

    Article  PubMed  CAS  Google Scholar 

  46. Ellis JA, Infantino T, Harrap SB. Sex-dependent association of blood pressure with oestrogen receptor genes ERalpha and ERbeta. J Hypertens. 2004;22:1127–31.

    Article  PubMed  CAS  Google Scholar 

  47. 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.

    Article  PubMed  CAS  Google Scholar 

  48. Dai-Do D, Espinosa E, Liu G, Rabelink TJ, Julmy F, Yang Z, et al. 17 beta-estradiol inhibits proliferation and migration of human vascular smooth muscle cells: similar effects in cells from postmenopausal females and in males. Cardiovasc Res. 1996;32:980–5.

    PubMed  CAS  Google Scholar 

  49. Kawano H, Motoyama T, Kugiyama K, Hirashima O, Ohgushi M, Fujii H, et al. Gender difference in improvement of endothelium-dependent vasodilation after estrogen supplementation. J Am Coll Cardiol. 1997;30:914–9.

    Article  PubMed  CAS  Google Scholar 

  50. New G, Timmins KL, Duffy SJ, Tran BT, O’Brien RC, Harper RW, et al. Long-term estrogen therapy improves vascular function in male to female transsexuals. J Am Coll Cardiol. 1997;29:1437–44.

    Article  PubMed  CAS  Google Scholar 

  51. Komesaroff PA, Fullerton M, Esler MD, Dart A, Jennings G, Sudhir K. Low-dose estrogen supplementation improves vascular function in hypogonadal men. Hypertension. 2001;38:1011–6.

    Article  PubMed  CAS  Google Scholar 

  52. Cavasin MA, Sankey SS, Yu AL, Menon S, Yang XP. 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:H1560–9.

    Article  PubMed  CAS  Google Scholar 

  53. Favre J, Vessieres E, Guihot AL, Grimaud L, Proux C, Loufrani L, et al. Early inactivation of membrane estrogen receptor alpha (ERalpha) recapitulates the endothelial dysfunction of aged mouse resistance arteries. Int J Mol Sci. 2022;23:2862.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Lin J, Steenbergen C, Murphy E, Sun J. Estrogen receptor-beta activation results in S-nitrosylation of proteins involved in cardioprotection. Circulation. 2009;120:245–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Gabel SA, Walker VR, London RE, Steenbergen C, Korach KS, Murphy E. Estrogen receptor beta mediates gender differences in ischemia/reperfusion injury. J Mol Cell Cardiol. 2005;38:289–97.

    Article  PubMed  CAS  Google Scholar 

  56. Makela S, Savolainen H, Aavik 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  PubMed Central  CAS  Google Scholar 

  57. Milner TA, Contoreggi NH, Yu F, Johnson MA, Wang G, Woods C, et al. Estrogen receptor beta contributes to both hypertension and hypothalamic plasticity in a mouse model of peri-menopause. J Neuroscii. 2021;41:5190–205.

    Article  CAS  Google Scholar 

  58. Xue B, Zhang Z, Beltz TG, Johnson RF, Guo F, Hay M, et al. Estrogen receptor-beta in the paraventricular nucleus and rostroventrolateral medulla plays an essential protective role in aldosterone/salt-induced hypertension in female rats. Hypertension. 2013;61:1255–62.

    Article  PubMed  CAS  Google Scholar 

  59. Lehrer S, Rabin J, Kalir T, Schachter BS. Estrogen receptor variant and hypertension in women. Hypertension. 1993;21:439–41.

    Article  PubMed  CAS  Google Scholar 

  60. Ogawa S, Emi M, Shiraki M, Hosoi T, Ouchi Y, Inoue S. Association of estrogen receptor beta (ESR2) gene polymorphism with blood pressure. J Hum Genet. 2000;45:327–30.

    Article  PubMed  CAS  Google Scholar 

  61. Manosroi W, Tan JW, Rariy CM, Sun B, Goodarzi MO, Saxena AR, et al. The Association of Estrogen Receptor-beta Gene Variation With Salt-Sensitive Blood Pressure. J Clin Endocrinol Metab. 2017;102:4124–35.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Thomas P, Pang Y, Filardo EJ, Dong J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 2005;146:624–32.

    Article  PubMed  CAS  Google Scholar 

  63. Lindsey SH, Liu L, Chappell MC. Vasodilation by GPER in mesenteric arteries involves both endothelial nitric oxide and smooth muscle cAMP signaling. Steroids. 2014;81:99–102.

    Article  PubMed  CAS  Google Scholar 

  64. Ogola BO, Zimmerman MA, Sure VN, Gentry KM, Duong JL, Clark GL, et al. G protein-coupled estrogen receptor protects from angiotensin II-induced increases in pulse pressure and oxidative stress. Front Endocrinol. 2019;10:586.

    Article  Google Scholar 

  65. Haas E, Bhattacharya I, Brailoiu E, Damjanovic M, Brailoiu GC, Gao X, et al. Regulatory role of G protein-coupled estrogen receptor for vascular function and obesity. Circ Res. 2009;104:288–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Ogola B, Zhang Y, Iyer L, Thekkumkara T. 2-Methoxyestradiol causes matrix metalloproteinase 9-mediated transactivation of epidermal growth factor receptor and angiotensin type 1 receptor downregulation in rat aortic smooth muscle cells. Am J Physiol Cell Physiol. 2018;314:C554–C568.

    Article  PubMed  CAS  Google Scholar 

  67. Lindsey SH, Cohen JA, Brosnihan KB, Gallagher PE, Chappell MC. Chronic treatment with the G protein-coupled receptor 30 agonist G-1 decreases blood pressure in ovariectomized mRen2.Lewis rats. Endocrinology. 2009;150:3753–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Alencar AK, Montes GC, Montagnoli T, Silva AM, Martinez ST, Fraga AG, et al. Activation of GPER ameliorates experimental pulmonary hypertension in male rats. Eur J Pharm Sci. 2017;97:208–17.

    Article  PubMed  CAS  Google Scholar 

  69. Dinh QN, Vinh A, Kim HA, Saini N, Broughton BRS, Chrissobolis S, et al. Aldosterone-induced hypertension is sex-dependent, mediated by T cells and sensitive to GPER activation. Cardiovasc Res. 2021;117:960–70.

    Article  PubMed  CAS  Google Scholar 

  70. Ogola BO, Clark GL, Abshire CM, Harris NR, Gentry KL, Gunda SS, et al. Sex and the G protein-coupled estrogen receptor impact vascular stiffness. Hypertension. 2021;78:e1–e14.

    Article  PubMed  CAS  Google Scholar 

  71. Broughton BR, Brait VH, Kim HA, Lee S, Chu HX, Gardiner-Mann CV, et al. Sex-dependent effects of G protein-coupled estrogen receptor activity on outcome after ischemic stroke. Stroke. 2014;45:835–41.

    Article  PubMed  CAS  Google Scholar 

  72. Meyer MR, Fredette NC, Daniel C, Sharma G, Amann K, Arterburn JB, et al. Obligatory role for GPER in cardiovascular aging and disease. Sci Signal. 2016;9:ra105.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Bian C, Bai B, Gao Q, Li S, Zhao Y. 17beta-Estradiol regulates glucose metabolism and insulin secretion in rat islet beta cells through GPER and Akt/mTOR/GLUT2 pathway. Front Endocrinol. 2019;10:531.

    Article  Google Scholar 

  74. Sharma G, Hu C, Staquicini DI, Brigman JL, Liu M, Mauvais-Jarvis F, et al. Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes. Sci Transl Med. 2020;12:eaau5956.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Lindsey SH, da Silva AS, Silva MS, Chappell MC. Reduced vasorelaxation to estradiol and G-1 in aged female and adult male rats is associated with GPR30 downregulation. Am J Physiol Endocrinol Metab. 2013;305:E113–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Yu X, Nguyen P, Burns NC, Heaps CL, Stallone JN, Sohrabji F, et al. Activation of G protein-coupled estrogen receptor fine-tunes age-related decreased vascular activities in the aortae of female and male rats. Steroids. 2022;183:108997.

    Article  PubMed  CAS  Google Scholar 

  77. Feldman RD, Gros R, Ding Q, Hussain Y, Ban MR, McIntyre AD, et al. A common hypofunctional genetic variant of GPER is associated with increased blood pressure in women. Br J Clin Pharmacol. 2014;78:1441–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Jessup JA, Lindsey SH, Wang H, Chappell MC, Groban L. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Wang H, Jessup JA, Lin MS, Chagas C, Lindsey SH, Groban L. Activation of GPR30 attenuates diastolic dysfunction and left ventricle remodelling in oophorectomized mRen2.Lewis rats. Cardiovascular Res. 2012;94:96–104.

    Article  CAS  Google Scholar 

  80. Wang H, Sun X, Chou J, Lin M, Ferrario CM, Zapata-Sudo G, et al. Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: a sex-specific gene profiling analysis. Biochim Biophys Acta Mol Basis Dis. 2017;1863:1870–82.

    Article  PubMed  CAS  Google Scholar 

  81. Wang H, Sun X, Chou J, Lin M, Ferrario CM, Zapata-Sudo G, et al. Inflammatory and mitochondrial gene expression data in GPER-deficient cardiomyocytes from male and female mice. Data brief. 2017;10:465–73.

    Article  PubMed  Google Scholar 

  82. Wang H, Sun X, Lin MS, Ferrario CM, Van Remmen H, Groban L. G protein-coupled estrogen receptor (GPER) deficiency induces cardiac remodeling through oxidative stress. Transl Res. 2018;199:39–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Lindsey SH, Yamaleyeva LM, Brosnihan KB, Gallagher PE, Chappell MC. Estrogen receptor GPR30 reduces oxidative stress and proteinuria in the salt-sensitive female mRen2.Lewis rat. Hypertension. 2011;58:665–71.

    Article  PubMed  CAS  Google Scholar 

  84. Gohar EY, Almutlaq RN, Daugherty EM, Butt MK, Jin C, Pollock JS, et al. Activation of G protein-coupled estrogen receptor 1 ameliorates proximal tubular injury and proteinuria in Dahl salt-sensitive female rats. Am J Physiol Regulatory Integr Comp Physiol. 2021;320:R297–R306.

    Article  CAS  Google Scholar 

  85. Delgado NTB, Rouver WDN, Freitas-Lima LC, Vieira-Alves I, Lemos VS, Dos Santos RL. Sex differences in the vasodilation mediated by G protein-coupled estrogen receptor (GPER) in hypertensive rats. Front Physiol. 2021;12:659291.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Collins P, Rosano GM, Sarrel PM, Ulrich L, Adamopoulos S, Beale CM, et al. 17 beta-Estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation. 1995;92:24–30.

    Article  PubMed  CAS  Google Scholar 

  87. Blumenthal RS, Heldman AW, Brinker JA, Resar JR, Coombs VJ, Gloth ST, et al. Acute effects of conjugated estrogens on coronary blood flow response to acetylcholine in men. Am J Cardiol. 1997;80:1021–4.

    Article  PubMed  CAS  Google Scholar 

  88. Reis SE, Holubkov R, Zell KA, Smith AJ, Cohen HA, Feldman MD, et al. Estrogen acutely abolishes abnormal cold-induced coronary constriction in men. Chest. 1998;114:1556–61.

    Article  PubMed  CAS  Google Scholar 

  89. Reis SE, Bhoopalam V, Zell KA, Counihan PJ, Smith AJ, Pham S, et al. Conjugated estrogens acutely abolish abnormal cold-induced coronary vasoconstriction in male cardiac allografts. Circulation. 1998;97:23–5.

    Article  PubMed  CAS  Google Scholar 

  90. Chappell MC. Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute? Am J Physiol Heart Circ Physiol. 2016;310:H137–52.

    Article  PubMed  Google Scholar 

  91. Medina D, Mehay D, Arnold AC. Sex differences in cardiovascular actions of the renin-angiotensin system. Clin Auton Res. 2020;30:393–408.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Yoo JK, Fu Q. Impact of sex and age on metabolism, sympathetic activity, and hypertension. FASEB J. 2020;34:11337–46.

    Article  PubMed  CAS  Google Scholar 

  93. Silva-Antonialli MM, Tostes RC, Fernandes L, Fior-Chadi DR, Akamine EH, Carvalho MH, et al. A lower ratio of AT1/AT2 receptors of angiotensin II is found in female than in male spontaneously hypertensive rats. Cardiovasc Res. 2004;62:587–93.

    Article  PubMed  CAS  Google Scholar 

  94. Pendergrass KD, Pirro NT, Westwood BM, Ferrario CM, Brosnihan KB, Chappell MC. Sex differences in circulating and renal angiotensins of hypertensive mRen(2). Lewis but not normotensive Lewis rats. Am J Physiol Heart Circ Physiol. 2008;295:H10–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Chappell MC, Gallagher PE, Averill DB, Ferrario CM, Brosnihan KB. Estrogen or the AT1 antagonist olmesartan reverses the development of profound hypertension in the congenic mRen2. Lewis rat. Hypertension. 2003;42:781–6.

    Article  PubMed  CAS  Google Scholar 

  96. Zhao YY, Zhou J, Narayanan CS, Cui Y, Kumar A. Role of C/A polymorphism at -20 on the expression of human angiotensinogen gene. Hypertension 1999;33:108–15.

    Article  PubMed  CAS  Google Scholar 

  97. Brosnihan KB, Hodgin JB, Smithies O, Maeda N, Gallagher P. 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;93:658–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Wang H, Jessup JA, Zhao Z, Da Silva J, Lin M, MacNamara LM, et al. Characterization of the cardiac renin angiotensin system in oophorectomized and estrogen-replete mRen2.Lewis rats. PLoS ONE. 2013;8:e76992.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Schunkert H, Danser AH, Hense HW, Derkx FH, Kurzinger S, Riegger GA. Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. Circulation. 1997;95:39–45.

    Article  PubMed  CAS  Google Scholar 

  100. Proudler AJ, Ahmed AI, Crook D, Fogelman I, Rymer JM, Stevenson JC. Hormone replacement therapy and serum angiotensin-converting-enzyme activity in postmenopausal women. Lancet. 1995;346:89–90.

    Article  PubMed  CAS  Google Scholar 

  101. Mauvais-Jarvis F, Berthold HK, Campesi I, Carrero JJ, Dakal S, Franconi F, et al. Sex- and gender-based pharmacological response to drugs. Pharmacol Rev. 2021;73:730–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, et al. A comparison of outcomes with angiotensin-converting−enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003;348:583–92.

    Article  PubMed  CAS  Google Scholar 

  103. Sung BH, Ching M, Izzo JL Jr., Dandona P, Wilson MF. Estrogen improves abnormal norepinephrine-induced vasoconstriction in postmenopausal women. J Hypertens. 1999;17:523–8.

    Article  PubMed  CAS  Google Scholar 

  104. Sudhir K, Elser MD, Jennings GL, Komesaroff PA. Estrogen supplementation decreases norepinephrine-induced vasoconstriction and total body norepinephrine spillover in perimenopausal women. Hypertension 1997;30:1538–43.

    Article  PubMed  CAS  Google Scholar 

  105. Li Z, Duckles SP. Influence of gender on vascular reactivity in the rat. J Pharmacol Exp Ther. 1994;268:1426–31.

    PubMed  CAS  Google Scholar 

  106. El-Mas MM, El-Gowilly SM, Gohar EY, Ghazal AR. Sex and hormonal influences on the nicotine-induced attenuation of isoprenaline vasodilations in the perfused rat kidney. Can J Physiol Pharmacol. 2009;87:539–48.

    Article  PubMed  CAS  Google Scholar 

  107. Riedel K, Deussen AJ, Tolkmitt J, Weber S, Schlinkert P, Zatschler B, et al. Estrogen determines sex differences in adrenergic vessel tone by regulation of endothelial beta-adrenoceptor expression. Am J Physiol Heart Circ Physiol. 2019;317:H243–H254.

    Article  PubMed  CAS  Google Scholar 

  108. Hajagos-Toth J, Bota J, Ducza E, Csanyi A, Tiszai Z, Borsodi A, et al. The effects of estrogen on the alpha2-adrenergic receptor subtypes in rat uterine function in late pregnancy in vitro. Croat Med J. 2016;57:100–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Freedman RR. Menopausal hot flashes: mechanisms, endocrinology, treatment. J Steroid Biochem Mol Biol. 2014;142:115–20.

    Article  PubMed  CAS  Google Scholar 

  110. Usselman CW, Gimon TI, Nielson CA, Luchyshyn TA, Coverdale NS, Van Uum SH, et al. Menstrual cycle and sex effects on sympathetic responses to acute chemoreflex stress. Am J Physiol Heart Circ Physiol. 2015;308:H664–71.

    Article  PubMed  CAS  Google Scholar 

  111. 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;101:862–8.

    Article  PubMed  CAS  Google Scholar 

  112. Jacob DW, Voshage AM, Harper JL, Limberg JK. Effect of oral hormonal contraceptive pill use on the hemodynamic response to the cold pressor test. Am J Physiol Heart Circ Physiol. 2022;322:H1072–H1079.

    Article  PubMed  CAS  Google Scholar 

  113. Mohamed MK, El-Mas MM, Abdel-Rahman AA. Estrogen enhancement of baroreflex sensitivity is centrally mediated. Am J Physiol. 1999;276:R1030–7.

    PubMed  CAS  Google Scholar 

  114. Huikuri HV, Pikkujamsa SM, Airaksinen KE, Ikaheimo MJ, Rantala AO, Kauma H, et al. Sex-related differences in autonomic modulation of heart rate in middle-aged subjects. Circulation. 1996;94:122–5.

    Article  PubMed  CAS  Google Scholar 

  115. Wang X, Khalil RA. Matrix metalloproteinases, vascular remodeling, and vascular disease. Adv Pharmacol. 2018;81:241–330.

    Article  PubMed  CAS  Google Scholar 

  116. Powell BS, Dhaher YY, Szleifer IG. Review of the multiscale effects of female sex hormones on matrix metalloproteinase-mediated collagen degradation. Crit Rev Biomed Eng. 2015;43:401–28.

    Article  PubMed  Google Scholar 

  117. Lau ES, Paniagua SM, Guseh JS, Bhambhani V, Zanni MV, Courchesne P, et al. Sex differences in circulating biomarkers of cardiovascular disease. J Am Coll Cardiol. 2019;74:1543–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Zhang Y, Stewart KG, Davidge ST. Estrogen replacement reduces age-associated remodeling in rat mesenteric arteries. Hypertension. 2000;36:970–4.

    Article  PubMed  CAS  Google Scholar 

  119. Arias-Loza PA, Hu K, Dienesch C, Mehlich AM, Konig S, Jazbutyte V, et al. Both estrogen receptor subtypes, alpha and beta, attenuate cardiovascular remodeling in aldosterone salt-treated rats. Hypertension. 2007;50:432–8.

    Article  PubMed  CAS  Google Scholar 

  120. Gros R, Hussain Y, Chorazyczewski J, Pickering JG, Ding Q, Feldman RD. Extent of vascular remodeling is dependent on the balance between estrogen receptor α and G-protein-coupled estrogen receptor. Hypertension. 2016;68:1225–35.

    Article  PubMed  CAS  Google Scholar 

  121. Dela Justina V, Miguez JSG, Priviero F, Sullivan JC, Giachini FR, Webb RC. Sex differences in molecular mechanisms of cardiovascular aging. Front Aging. 2021;2:725884.

    Article  Google Scholar 

  122. Laakkonen EK, Karppinen JE, Lehti S, Lee E, Pesonen E, Juppi HK, et al. Associations of sex hormones and hormonal status with arterial stiffness in a female sample from reproductive years to menopause. Front Endocrinol. 2021;12:765916.

    Article  Google Scholar 

  123. Nagai Y, Earley CJ, Kemper MK, Bacal CS, Metter EJ. Influence of age and postmenopausal estrogen replacement therapy on carotid arterial stiffness in women. Cardiovasc Res. 1999;41:307–11.

    Article  PubMed  CAS  Google Scholar 

  124. Samargandy S, Matthews KA, Brooks MM, Barinas-Mitchell E, Magnani JW, Janssen I, et al. Arterial stiffness accelerates within 1 year of the final menstrual period: the SWAN Heart Study. Arteriosclerosis Thrombosis, Vasc Biol. 2020;40:1001–8.

    Article  CAS  Google Scholar 

  125. Ogola BO, Abshire CM, Visniauskas B, Kiley JX, Horton AC, Clark GL, et al. Sex differences in vascular aging and impact of GPER deletion. Am J Physiol Heart Circ Physiol. 2022;323:H336–H349.

    Article  PubMed  CAS  Google Scholar 

  126. Manrique C, Lastra G, Ramirez-Perez FI, Haertling D, DeMarco VG, Aroor AR, et al. Endothelial estrogen receptor-alpha does not protect against vascular stiffness induced by western diet in female mice. Endocrinology. 2016;157:1590–600.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Manrique-Acevedo C, Ramirez-Perez FI, Padilla J, Vieira-Potter VJ, Aroor AR, Barron BJ, et al. Absence of endothelial ERalpha results in arterial remodeling and decreased stiffness in western diet-fed male mice. Endocrinology. 2017;158:1875–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. DuPont JJ, Kim SK, Kenney RM, Jaffe IZ. Sex differences in the time course and mechanisms of vascular and cardiac aging in mice: role of the smooth muscle cell mineralocorticoid receptor. Am J Physiol Heart Circ Physiol. 2021;320:H169–H180.

    Article  PubMed  CAS  Google Scholar 

  129. Demirkiran A, Everaars H, Elitok A, van de Ven PM, Smulders YM, Dreijerink KM, et al. Hypertension with primary aldosteronism is associated with increased carotid intima-media thickness and endothelial dysfunction. J Clin Hypertens (Greenwich). 2019;21:932–41.

    Article  CAS  Google Scholar 

  130. Powell-Wiley TM, Poirier P, Burke LE, Despres JP, Gordon-Larsen P, Lavie CJ, et al. Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2021;143:e984–e1010.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Stierman B, Afful J, Carroll MD, Chen T, Davy O, Fink S, et al. National Health and Nutrition Examination Survey 2017–March 2020 prepandemic data files development of files and prevalence estimates for selected health outcomes. Natl Health Stats Rep. 2021;158:1–21.

    Google Scholar 

  132. Lovre D, Lindsey SH, Mauvais-Jarvis F. Effect of menopausal hormone therapy on components of the metabolic syndrome. Ther Adv Cardiovasc Dis. 2016;11:33–43.

    Article  PubMed Central  Google Scholar 

  133. Law J, Bloor I, Budge H, Symonds ME. The influence of sex steroids on adipose tissue growth and function. Horm Mol Biol Clin Investig. 2014;19:13–24.

    PubMed  CAS  Google Scholar 

  134. Sharma G, Mauvais-Jarvis F, Prossnitz ER. Roles of G protein-coupled estrogen receptor GPER in metabolic regulation. J Steroid Biochem Mol Biol. 2018;176:31–37.

    Article  PubMed  CAS  Google Scholar 

  135. Hellstrom L, Wahrenberg H, Hruska K, Reynisdottir S, Arner P. Mechanisms behind gender differences in circulating leptin levels. J Intern Med. 2000;247:457–62.

    Article  PubMed  CAS  Google Scholar 

  136. Huby AC, Otvos L Jr., Belin de Chantemele EJ. Leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in obese female mice. Hypertension. 2016;67:1020–8.

    Article  PubMed  CAS  Google Scholar 

  137. Haffner SM, Mykkanen L, Stern MP. Leptin concentrations in women in the San Antonio Heart Study: effect of menopausal status and postmenopausal hormone replacement therapy. Am J Epidemiol. 1997;146:581–5.

    Article  PubMed  CAS  Google Scholar 

  138. Salbach B, Nawroth PP, Kubler W, von Holst T, Salbach PB. Serum leptin levels and body weight in postmenopausal women under transdermal hormone replacement therapy. Eur J Med Res. 2000;5:63–6.

    PubMed  CAS  Google Scholar 

  139. Roesch DM, Tian Y, Zheng W, Shi M, Verbalis JG, Sandberg K. Estradiol attenuates angiotensin-induced aldosterone secretion in ovariectomized rats. Endocrinology. 2000;141:4629–36.

    Article  PubMed  CAS  Google Scholar 

  140. Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol. 2014;35:347–69.

    Article  PubMed  CAS  Google Scholar 

  141. Desai MK, Brinton RD. Autoimmune disease in women: endocrine transition and risk across the lifespan. Front Endocrinol. 2019;10:265.

    Article  Google Scholar 

  142. Castro-Gutierrez A, Young K, Bermas BL. Pregnancy and management in women with rheumatoid arthritis, systemic lupus erythematosus, and obstetric antiphospholipid syndrome. Rheum Dis Clin N Am. 2022;48:523–35.

    Article  Google Scholar 

  143. Cutolo M, Brizzolara R, Atzeni F, Capellino S, Straub RH, Puttini PC. The immunomodulatory effects of estrogens: clinical relevance in immune-mediated rheumatic diseases. Ann N Y Acad Sci. 2010;1193:36–42.

    Article  PubMed  CAS  Google Scholar 

  144. Verthelyi D. Sex hormones as immunomodulators in health and disease. Int Immunopharmacol. 2001;1:983–93.

    Article  PubMed  CAS  Google Scholar 

  145. Lewis PA, O’Sullivan MM, Rumfeld WR, Coles EC, Jessop JD. Significant changes in Ritchie scores. Br J Rheumatol. 1988;27:32–6.

    Article  PubMed  CAS  Google Scholar 

  146. Zhang MA, Rego D, Moshkova M, Kebir H, Chruscinski A, Nguyen H, et al. Peroxisome proliferator-activated receptor (PPAR)alpha and -gamma regulate IFNgamma and IL-17A production by human T cells in a sex-specific way. Proc Natl Acad Sci USA. 2012;109:9505–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Yang J, Chu Y, Yang X, Gao D, Zhu L, Yang X, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009;60:1472–83.

    Article  PubMed  Google Scholar 

  148. Wolf VL, Ryan MJ. Autoimmune disease-associated hypertension. Curr Hypertens Rep. 2019;21:10.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Pollow DP, Uhrlaub J, Romero-Aleshire M, Sandberg K, Nikolich-Zugich J, Brooks HL, et al. Sex differences in T-lymphocyte tissue infiltration and development of angiotensin II hypertension. Hypertension. 2014;64:384–90.

    Article  PubMed  CAS  Google Scholar 

  150. Pollow DP Jr., Uhlorn JA, Sylvester MA, Romero-Aleshire MJ, Uhrlaub JL, Lindsey ML, et al. Menopause and FOXP3(+) Treg cell depletion eliminate female protection against T cell-mediated angiotensin II hypertension. Am J Physiol Heart Circ Physiol. 2019;317:H415–H423.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Witkowski M, Weeks TL, Hazen SL. Gut microbiota and cardiovascular disease. Circ Res. 2020;127:553–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Koren O, Spor A, Felin J, Fak F, Stombaugh J, Tremaroli V, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci USA. 2011;108:4592–8.

    Article  PubMed  CAS  Google Scholar 

  153. Li J, Zhao F, Wang Y, Chen J, Tao J, Tian G, et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome. 2017;5:14.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Jumpertz R, Le DS, Turnbaugh PJ, Trinidad C, Bogardus C, Gordon JI, et al. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am J Clin Nutr. 2011;94:58–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci USA. 2005;102:11070–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Chen C, Gong X, Yang X, Shang X, Du Q, Liao Q, et al. The roles of estrogen and estrogen receptors in gastrointestinal disease. Oncol Lett. 2019;18:5673–80.

    PubMed  PubMed Central  CAS  Google Scholar 

  157. Leite G, Barlow GM, Parodi G, Pimentel ML, Chang C, Hosseini A, et al. Duodenal microbiome changes in postmenopausal women: effects of hormone therapy and implications for cardiovascular risk. Menopause. 2022;29:264–75.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Liu L, Fu Q, Li T, Shao K, Zhu X, Cong Y, et al. Gut microbiota and butyrate contribute to nonalcoholic fatty liver disease in premenopause due to estrogen deficiency. PLoS ONE. 2022;17:e0262855.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Kasper P, Martin A, Lang S, Kutting F, Goeser T, Demir M, et al. NAFLD and cardiovascular diseases: a clinical review. Clin Res Cardiol. 2021;110:921–37.

    Article  PubMed  Google Scholar 

  160. Balafa O, Kalaitzidis RG. Salt sensitivity and hypertension. J Hum Hypertens. 2021;35:184–92.

    Article  PubMed  Google Scholar 

  161. Colafella KMM, Denton KM. Sex-specific differences in hypertension and associated cardiovascular disease. Nat Rev Nephrol. 2018;14:185–201.

    Article  PubMed  Google Scholar 

  162. Veiras LC, Girardi ACC, Curry J, Pei L, Ralph DL, Tran A, et al. Sexual dimorphic pattern of renal transporters and electrolyte homeostasis. J Am Soc Nephrol. 2017;28:3504–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Dahl LK, Knudsen KD, Ohanian EV, Muirhead M, Tuthill R. Role of the gonads in hypertension-prone rats. J Exp Med. 1975;142:748–59.

    Article  PubMed  CAS  Google Scholar 

  164. Kittikulsuth W, Sullivan JC, Pollock DM. ET-1 actions in the kidney: evidence for sex differences. Br J Pharmacol. 2013;168:318–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Yamaleyeva LM, Pendergrass KD, Pirro NT, Gallagher PE, Groban L, Chappell MC. Ovariectomy is protective against renal injury in the high-salt-fed older mRen2. Lewis rat. Am J Physiol Heart Circ Physiol. 2007;293:H2064–71.

    Article  PubMed  CAS  Google Scholar 

  166. Douma LG, Gumz ML. Circadian clock-mediated regulation of blood pressure. Free Radic Biol Med. 2018;119:108–14.

    Article  PubMed  CAS  Google Scholar 

  167. Rhoads MK, Balagee V, Thomas SJ. Circadian regulation of blood pressure: of mice and men. Curr Hypertens Rep. 2020;22:40.

    Article  PubMed  PubMed Central  Google Scholar 

  168. Sherwood A, Steffen PR, Blumenthal JA, Kuhn C, Hinderliter AL. Nighttime blood pressure dipping: the role of the sympathetic nervous system. Am J Hypertens. 2002;15:111–8. 2 Pt 1

    Article  PubMed  Google Scholar 

  169. Agarwal R. Regulation of circadian blood pressure: from mice to astronauts. Curr Opin Nephrol hypertension. 2010;19:51–8.

    Article  Google Scholar 

  170. Ohashi N, Isobe S, Ishigaki S, Yasuda H. Circadian rhythm of blood pressure and the renin-angiotensin system in the kidney. Hypertens Res. 2017;40:413–22.

    Article  PubMed  CAS  Google Scholar 

  171. Boggia J, Thijs L, Hansen TW, Li Y, Kikuya M, Bjorklund-Bodegard K, et al. Ambulatory blood pressure monitoring in 9357 subjects from 11 populations highlights missed opportunities for cardiovascular prevention in women. Hypertension. 2011;57:397–405.

    Article  PubMed  CAS  Google Scholar 

  172. Nicolaides NC, Chrousos GP. Sex differences in circadian endocrine rhythms: clinical implications. Eur J Neurosci. 2020;52:2575–85.

    Article  PubMed  Google Scholar 

  173. Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Sacchi N, Battistelli M, et al. Gender, day-night blood pressure changes, and left ventricular mass in essential hypertension. Dippers and peakers. Am J Hypertens. 1995;8:193–6.

    Article  PubMed  CAS  Google Scholar 

  174. Routledge FS, McFetridge-Durdle JA, Dean CR. Stress, menopausal status and nocturnal blood pressure dipping patterns among hypertensive women. Can J Cardiol. 2009;25:e157–63.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Mercuro G, Zoncu S, Pilia I, Lao A, Melis GB, Cherchi A. Effects of acute administration of transdermal estrogen on postmenopausal women with systemic hypertension. Am J Cardiol. 1997;80:652–5.

    Article  PubMed  CAS  Google Scholar 

  176. Mercuro G, Zoncu S, Piano D, Pilia I, Lao A, Melis GB, et al. Estradiol-17beta reduces blood pressure and restores the normal amplitude of the circadian blood pressure rhythm in postmenopausal hypertension. Am J Hypertens. 1998;11:909–13. 8 Pt 1

    Article  PubMed  CAS  Google Scholar 

  177. Foderaro A, Ventetuolo CE. Pulmonary arterial hypertension and the sex hormone paradox. Curr Hypertens Rep. 2016;18:84.

    Article  PubMed  Google Scholar 

  178. Hester J, Ventetuolo C, Lahm T. Sex, gender, and sex hormones in pulmonary hypertension and right ventricular failure. Compr Physiol. 2019;10:125–70.

    Article  PubMed  PubMed Central  Google Scholar 

  179. Mair KM, Johansen AK, Wright AF, Wallace E, MacLean MR. Pulmonary arterial hypertension: basis of sex differences in incidence and treatment response. Br J Pharmacol. 2014;171:567–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Umar S, Rabinovitch M, Eghbali M. Estrogen paradox in pulmonary hypertension: current controversies and future perspectives. Am J Respir Crit Care Med. 2012;186:125–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Earley S, Resta TC. Estradiol attenuates hypoxia-induced pulmonary endothelin-1 gene expression. Am J Physiol Lung Cell Mol Physiol. 2002;283:L86–93.

    Article  PubMed  CAS  Google Scholar 

  182. Umar S, Iorga A, Matori H, Nadadur RD, Li J, Maltese F, et al. Estrogen rescues preexisting severe pulmonary hypertension in rats. Am J Respir Crit Care Med. 2011;184:715–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Taraseviciute A, Voelkel NF. Severe pulmonary hypertension in postmenopausal obese women. Eur J Med Res. 2006;11:198–202.

    PubMed  Google Scholar 

  184. Chen X, Austin ED, Talati M, Fessel JP, Farber-Eger EH, Brittain EL, et al. Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects. Eur Respir J. 2017;50:1602337.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Day S, Mason R, Lagosky S, Rochon PA. Integrating and evaluating sex and gender in health research. Health Res Policy Syst. 2016;14:75.

    Article  PubMed  PubMed Central  Google Scholar 

  186. Rompel S, Schneider A, Peters A, Kraus U, On Behalf Of The Inger Study G. Sex/gender-differences in the health effects of environmental noise exposure on hypertension and ischemic heart disease-a systematic review. Int J Environ Res Public Health. 2021;18:9856.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Everett B, Zajacova A. Gender differences in hypertension and hypertension awareness among young adults. Biodemography Soc Biol. 2015;61:1–17.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Bertakis KD, Azari R, Helms LJ, Callahan EJ, Robbins JA. Gender differences in the utilization of health care services. J Fam Pr. 2000;49:147–52.

    CAS  Google Scholar 

  189. Turner ST, Schwartz GL, Chapman AB, Beitelshees AL, Gums JG, Cooper-DeHoff RM, et al. Plasma renin activity predicts blood pressure responses to beta-blocker and thiazide diuretic as monotherapy and add-on therapy for hypertension. Am J Hypertens. 2010;23:1014–22.

    Article  PubMed  CAS  Google Scholar 

  190. Gueyffier F, Subtil F, Bejan-Angoulvant T, Zerbib Y, Baguet JP, Boivin JM, et al. Can we identify response markers to antihypertensive drugs? First results from the IDEAL Trial. J Hum Hypertens. 2015;29:22–7.

    Article  PubMed  CAS  Google Scholar 

  191. Vlassoff C. Gender differences in determinants and consequences of health and illness. J Health Popul Nutr. 2007;25:47–61.

    PubMed  PubMed Central  Google Scholar 

  192. Neufcourt L, Deguen S, Bayat S, Paillard F, Zins M, Grimaud O. Geographical variations in the prevalence of hypertension in France: Cross-sectional analysis of the CONSTANCES cohort. Eur J Prev Cardiol. 2019;26:1242–51.

    Article  PubMed  Google Scholar 

  193. Vijna, Mishra CP. Prevalence and predictors of hypertension: evidence from a study of rural India. J Fam Med Prim Care. 2022;11:1047–54.

    Article  CAS  Google Scholar 

  194. Steinberg JR, Turner BE, Weeks BT, Magnani CJ, Wong BO, Rodriguez F, et al. Analysis of female enrollment and participant sex by burden of disease in US clinical trials between 2000 and 2020. JAMA Netw Open. 2021;4:e2113749.

    Article  PubMed  PubMed Central  Google Scholar 

  195. Bartlett C, Doyal L, Ebrahim S, Davey P, Bachmann M, Egger M, et al. The causes and effects of socio-demographic exclusions from clinical trials. Health Technol Assess. 2005;9:1–152. iii-iv, ix-x.

    Article  Google Scholar 

  196. Miller MA. Gender-based differences in the toxicity of pharmaceuticals−the Food and Drug Administration’s perspective. Int J Toxicol. 2001;20:149–52.

    Article  PubMed  CAS  Google Scholar 

  197. Ferdinand KC. Cardiovascular disease in blacks: can we stop the clock? J Clin Hypertens. 2008;10:382–9.

    Article  Google Scholar 

  198. Coylewright M, Reckelhoff JF, Ouyang P. Menopause and hypertension: an age-old debate. Hypertension. 2008;51:952–9.

    Article  PubMed  CAS  Google Scholar 

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Funding

This work was supported by the National Institutes of Health (HL133619 and AG071746 to SHL; HL155841 to BOO), the American Heart Association (829713 to BV; 827812 to IKD), and the Tulane Center of Excellence in Sex-Based Biology & Medicine.

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Visniauskas, B., Kilanowski-Doroh, I., Ogola, B.O. et al. Estrogen-mediated mechanisms in hypertension and other cardiovascular diseases. J Hum Hypertens (2022). https://doi.org/10.1038/s41371-022-00771-0

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