Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Sex-specific differences in hypertension and associated cardiovascular disease

Nature Reviews Nephrology volume 14, pages 185–201 (2018)Cite this article

Subjects

Key Points

  • Although blood pressure (BP) is lower in women than in men during the reproductive years, 50% of all cardiovascular disease (CVD)-related deaths occur in women, resulting in a greater incidence of CVD in older women than in age-matched men.

  • The same mechanisms that regulate BP and cardiovascular function are present in both men and women, but these systems are shifted towards cardioprotective pathways in women between puberty and menopause.

  • Sex hormones such as oestrogen and testosterone have a role in cardioprotection by modulating vasodilator and vasoconstrictor pathways, including the renin–angiotensin–aldosterone system (RAAS) and the endothelin system.

  • The sex chromosome complement can act independently of sex hormone effects, which results in sex-specific, age-specific and tissue-specific differences in gene transcription.

  • Obesity affects more women than men; as obesity is associated with a loss of cardioprotection, CVD occurs at an earlier age in obese women than in lean women.

  • Women have a longer lifespan than men and develop age-related and CVD-related pathologies later in life; these beneficial outcomes might be due in part to sex differences in cell injury and repair pathways that delay the chronic accumulation of senescent cells, end-organ damage and the progression of CVD.

Abstract

Although intrinsic mechanisms that regulate arterial blood pressure (BP) are similar in men and women, marked variations exist at the molecular, cellular and tissue levels. These physiological disparities between the sexes likely contribute to differences in disease onset, susceptibility, prevalence and treatment responses. Key systems that are important in the development of hypertension and cardiovascular disease (CVD), including the sympathetic nervous system, the renin–angiotensin–aldosterone system and the immune system, are differentially activated in males and females. Biological age also contributes to sexual dimorphism, as premenopausal women experience a higher degree of cardioprotection than men of similar age. Furthermore, sex hormones such as oestrogen and testosterone as well as sex chromosome complement likely contribute to sex differences in BP and CVD. At the cellular level, differences in cell senescence pathways may contribute to increased longevity in women and may also limit organ damage caused by hypertension. In addition, many lifestyle and environmental factors — such as smoking, alcohol consumption and diet — may influence BP and CVD in a sex-specific manner. Evidence suggests that cardioprotection in women is lost under conditions of obesity and type 2 diabetes mellitus. Treatment strategies for hypertension and CVD that are tailored according to sex could lead to improved outcomes for affected patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Determinants of cardiovascular risk over a lifetime.
Figure 2: Blood pressure changes in both sexes across the lifespan.
Figure 3: Sex differences in cellular senescence pathways in response to age-induced and disease-induced damage.
Figure 4: Contributing factors of cardioprotection, hypertension and cardiovascular disease.

Similar content being viewed by others

References

  1. WHO. Fact Sheet: noncommunicable diseases. WHO http://www.who.int/mediacentre/factsheets/fs355/en/(2015).

  2. Mehta, L. S. et al. Acute myocardial infarction in women: a scientific statement from the American Heart Association. Circulation 133, 916–947 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Benjamin, E. J. et al. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation 135, e146–e603 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Rabi, D. M. et al. Reporting on sex-based analysis in clinical trials of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker efficacy. Can. J. Cardiol. 24, 491–496 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Go, A. S. et al. Heart disease and stroke statistics — 2014 update: a report from the American Heart Association. Circulation 129, e28–e292 (2014).

    Article  PubMed  CAS  Google Scholar 

  6. Ventura-Clapier, R. et al. Sex in basic research: concepts in the cardiovascular field. Cardiovasc. Res. 113, 711–724 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Dayton, A. et al. Breaking the cycle: estrous variation does not require increased sample size in the study of female rats. Hypertension 68, 1139–1144 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Smarr, B. L., Grant, A. D., Zucker, I., Prendergast, B. J. & Kriegsfeld, L. J. Sex differences in variability across timescales in BALB/c mice. Biol. Sex. Differ. 8, 7 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Kim, A. M., Tingen, C. M. & Woodruff, T. K. Sex bias in trials and treatment must end. Nature 465, 688–689 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Beery, A. K. & Zucker, I. Sex bias in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 35, 565–572 (2011).

    Article  PubMed  Google Scholar 

  11. Maric-Bilkan, C. & Galis, Z. S. Trends in NHLBI-funded research on sex differences in hypertension. Circ. Res. 119, 591–595 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Clayton, J. A. & Collins, F. S. Policy: NIH to balance sex in cell and animal studies. Nature 509, 282–283 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Austad, S. N. & Bartke, A. Sex differences in longevity and in responses to anti-aging interventions: a mini-review. Gerontology 62, 40–46 (2015).

    Article  PubMed  CAS  Google Scholar 

  14. Stark, M. J., Clifton, V. L. & Wright, I. M. Sex-specific differences in peripheral microvascular blood flow in preterm infants. Pediatr. Res. 63, 415–419 (2008).

    Article  PubMed  Google Scholar 

  15. Ishiguro, A. et al. Changes in skin and subcutaneous perfusion in very-low-birth-weight infants during the transitional period. Neonatology 100, 162–168 (2011).

    Article  PubMed  Google Scholar 

  16. Schwepcke, A., Weber, F. D., Mormanova, Z., Cepissak, B. & Genzel-Boroviczeny, O. Microcirculatory mechanisms in postnatal hypotension affecting premature infants. Pediatr. Res. 74, 186–190 (2013).

    Article  PubMed  Google Scholar 

  17. Stark, M. J., Clifton, V. L. & Wright, I. M. Microvascular flow, clinical illness severity and cardiovascular function in the preterm infant. Arch. Dis. Child Fetal Neonatal Ed 93, F271–F274 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Brown, R. D. et al. Reduced sensitivity of the renal vasculature to angiotensin II in young rats: the role of the angiotensin type 2 receptor. Pediatr. Res. 76, 448–452 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Barsha, G., Denton, K. M. & Mirabito Colafella, K. M. Sex- and age-related differences in arterial pressure and albuminuria in mice. Biol. Sex. Differ. 7, 57 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hilliard, L. M., Sampson, A. K., Brown, R. D. & Denton, K. M. The “his and hers” of the renin−angiotensin system. Curr. Hypertens. Rep. 15, 71–79 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Wiinberg, N. et al. 24-h ambulatory blood pressure in 352 normal Danish subjects, related to age and gender. Am. J. Hypertens. 8, 978–986 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Baik, N. et al. Blood pressure during the immediate neonatal transition: is the mean arterial blood pressure relevant for the cerebral regional oxygenation? Neonatology 112, 97–102 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Flynn, J. T. et al. Update: ambulatory blood pressure monitoring in children and adolescents: a scientific statement from the American Heart Association. Hypertension 63, 1116–1135 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Shen, W. et al. Race and sex differences of long-term blood pressure profiles from childhood and adult hypertension: the Bogalusa heart study. Hypertension 70, 66–74 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Stamler, J., Dyer, A. R., Shekelle, R. B., Neaton, J. & Stamler, R. Relationship of baseline major risk factors to coronary and all-cause mortality, and to longevity: findings from long-term follow-up of Chicago cohorts. Cardiology 82, 191–222 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Stamler, J., Stamler, R., Riedlinger, W. F., Algera, G. & Roberts, R. H. Hypertension screening of 1 million Americans. Community Hypertension Evaluation Clinic (CHEC) program, 1973 through 1975. JAMA 235, 2299–2306 (1976).

    Article  CAS  PubMed  Google Scholar 

  27. Whelton, P. K. et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension https://doi.org/10.1161/HYP.0000000000000065 (2017).

  28. Pilote, L. et al. A comprehensive view of sex-specific issues related to cardiovascular disease. CMAJ 176, S1–S44 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Silbiger, S. & Neugarten, J. Gender and human chronic renal disease. Gend Med. 5 (Suppl. A), S3–S10 (2008).

    Article  PubMed  Google Scholar 

  30. Cadeddu, C. et al. Arterial hypertension in the female world: pathophysiology and therapy. J. Cardiovasc. Med. (Hagerstown) 17, 229–236 (2016).

    Article  CAS  Google Scholar 

  31. Miller, J. A. et al. Gender differences in the renal response to renin-angiotensin system blockade. J. Am. Soc. Nephrol. 17, 2554–2560 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Hudson, M., Rahme, E., Behlouli, H., Sheppard, R. & Pilote, L. Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure—a population study. Eur. J. Heart Fail 9, 602–609 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Hall, J. E. The kidney, hypertension, and obesity. Hypertension 41, 625–633 (2003).

    Article  PubMed  CAS  Google Scholar 

  34. Glassock, R. J. & Rule, A. D. Aging and the kidneys: anatomy, physiology and consequences for defining chronic kidney disease. Nephron 134, 25–29 (2016).

    Article  PubMed  Google Scholar 

  35. Denic, A., Glassock, R. J. & Rule, A. D. Structural and functional changes with the aging kidney. Adv. Chron. Kidney Dis. 23, 19–28 (2016).

    Article  Google Scholar 

  36. Denic, A. et al. The substantial loss of nephrons in healthy human kidneys with aging. J. Am. Soc. Nephrol. 28, 313–320 (2017).

    Article  PubMed  Google Scholar 

  37. Denic, A. et al. Single-nephron glomerular filtration rate in healthy adults. N. Engl. J. Med. 376, 2349–2357 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Gekle, M. Kidney and aging — a narrative review. Exp. Gerontol. 87, 153–155 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Hoy, W. E. et al. A stereological study of glomerular number and volume: preliminary findings in a multiracial study of kidneys at autopsy. Kidney Int. 63 (Suppl. 83), S31–S37 (2003).

    Article  Google Scholar 

  40. Mallappallil, M., Friedman, E. A., Delano, B. G., McFarlane, S. I. & Salifu, M. O. Chronic kidney disease in the elderly: evaluation and management. Clin. Pract. (Lond.) 11, 525–535 (2014).

    Article  CAS  Google Scholar 

  41. Prakash, S. & O'Hare, A. M. Interaction of aging and chronic kidney disease. Semin. Nephrol. 29, 497–503 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Ivy, J. R. & Bailey, M. A. Pressure natriuresis and the renal control of arterial blood pressure. J. Physiol. 592, 3955–3967 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hall, J. E. Renal dysfunction, rather than nonrenal vascular dysfunction, mediates salt-induced hypertension. Circulation 133, 894–906 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Khraibi, A. A., Liang, M. & Berndt, T. J. Role of gender on renal interstitial hydrostatic pressure and sodium excretion in rats. Am. J. Hypertens. 14, 893–896 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Mirabito, K. M. et al. Sex- and age-related differences in the chronic pressure-natriuresis relationship: role of the angiotensin type 2 receptor. Am. J. Physiol. Renal Physiol. 307, F901–F907 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Tominaga, T., Suzuki, H., Ogata, Y., Matsukawa, S. & Saruta, T. The role of sex hormones and sodium intake in postmenopausal hypertension. J. Hum. Hypertens. 5, 495–500 (1991).

    CAS  PubMed  Google Scholar 

  47. Martillotti, G. et al. Increased salt sensitivity of ambulatory blood pressure in women with a history of severe preeclampsia. Hypertension 62, 802–808 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Veiras, L. C. et al. Sexual dimorphic pattern of renal transporters and electrolyte homeostasis. J. Am. Soc. Nephrol. 28, 3504–3517 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sturmlechner, I., Durik, M., Sieben, C. J., Baker, D. J. & van Deursen, J. M. Cellular senescence in renal ageing and disease. Nat. Rev. Nephrol. 13, 77–89 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. de Cavanagh, E. M., Inserra, F. & Ferder, L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am. J. Physiol. Heart Circ. Physiol. 309, H15–H44 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Karalliedde, J., Maltese, G., Hill, B., Viberti, G. & Gnudi, L. Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria. Clin. J. Am. Soc. Nephrol. 8, 1899–1905 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kim, H. et al. Anti-fibrotic effect of losartan, an angiotensin II receptor blocker, is mediated through inhibition of ER stress via up-regulation of SIRT1, Followed by induction of HO-1 and thioredoxin. Int. J. Mol. Sci. 18, 305 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  53. Weidmann, P., De Myttenaere-Bursztein, S., Maxwell, M. H. & de Lima, J. Effect on aging on plasma renin and aldosterone in normal man. Kidney Int. 8, 325–333 (1975).

    Article  CAS  PubMed  Google Scholar 

  54. Tank, J. E., Vora, J. P., Houghton, D. C. & Anderson, S. Altered renal vascular responses in the aging rat kidney. Am. J. Physiol. 266, F942–F948 (1994).

    CAS  PubMed  Google Scholar 

  55. Pawluczyk, I. Z. & Harris, K. P. Effect of angiotensin type 2 receptor over-expression on the rat mesangial cell fibrotic phenotype: effect of gender. J. Renin Angiotensin Aldosterone Syst. 13, 221–231 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Pawluczyk, I. Z., Tan, E. K. & Harris, K. P. Rat mesangial cells exhibit sex-specific profibrotic and proinflammatory phenotypes. Nephrol. Dial. Transplant. 24, 1753–1758 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Barrett, E. L. & Richardson, D. S. Sex differences in telomeres and lifespan. Aging Cell 10, 913–921 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Tarry-Adkins, J. L., Ozanne, S. E., Norden, A., Cherif, H. & Hales, C. N. Lower antioxidant capacity and elevated p53 and p21 may be a link between gender disparity in renal telomere shortening, albuminuria, and longevity. Am. J. Physiol. Renal Physiol. 290, F509–F516 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Walker, A. E. et al. Age-related arterial telomere uncapping and senescence is greater in women compared with men. Exp. Gerontol. 73, 65–71 (2016).

    Article  CAS  PubMed  Google Scholar 

  61. Morgan, R. G. et al. Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping. J. Hypertens. 32, 1293–1299 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Batsis, J. A. et al. Association of adiposity, telomere length and mortality: data from the NHANES 1999–2002. Int. J. Obes. https://doi.org/10.1038/ijo.2017.202 (2017).

  63. Hoppel, C. L., Lesnefsky, E. J., Chen, Q. & Tandler, B. Mitochondrial dysfunction in cardiovascular aging. Adv. Exp. Med. Biol. 982, 451–464 (2017).

    Article  CAS  PubMed  Google Scholar 

  64. Wolf, D. P., Hayama, T. & Mitalipov, S. Mitochondrial genome inheritance and replacement in the human germline. EMBO J. 36, 2659 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Latorre-Pellicer, A. et al. Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature 535, 561–565 (2016).

    Article  CAS  PubMed  Google Scholar 

  66. Ventura-Clapier, R. et al. Mitochondria: a central target for sex differences in pathologies. Clin. Sci. 131, 803–822 (2017).

    Article  CAS  Google Scholar 

  67. Lagranha, C. J., Deschamps, A., Aponte, A., Steenbergen, C. & Murphy, E. Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females. Circ. Res. 106, 1681–1691 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pereira, S. P. et al. Effects of moderate global maternal nutrient reduction on fetal baboon renal mitochondrial gene expression at 0.9 gestation. Am. J. Physiol. Renal Physiol. 308, F1217–F1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kett, M. M. & Denton, K. M. Renal programming: cause for concern? Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, R791–R803 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Dubey, R. K., Oparil, S., Imthurn, B. & Jackson, E. K. Sex hormones and hypertension Cardiovasc. Res. 53, 688–708 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Reckelhoff, J. F. Gender differences in the regulation of blood pressure. Hypertension 37, 1199–1208 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Butkevich, A., Abraham, C. & Phillips, R. A. Hormone replacement therapy and 24-hour blood pressure profile of postmenopausal women. Am. J. Hypertens. 13, 1039–1041 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Cacciatore, B. et al. Randomized comparison between orally and transdermally administered hormone replacement therapy regimens of long-term effects on 24-hour ambulatory blood pressure in postmenopausal women. Am. J. Obstet. Gynecol. 184, 904–909 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Szekacs, B. et al. Hormone replacement therapy reduces mean 24-hour blood pressure and its variability in postmenopausal women with treated hypertension. Menopause 7, 31–35 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Crane, M. G., Harris, J. J. & Winsor, W. 3rd. Hypertension, oral contraceptive agents, and conjugated estrogens. Ann. Intern. Med. 74, 13–21 (1971).

    Article  CAS  PubMed  Google Scholar 

  76. Notelovitz, M. Effect of natural oestrogens on blood pressure and weight in postmenopausal women. S. Afr. Med. J. 49, 2251–2254 (1975).

    CAS  PubMed  Google Scholar 

  77. Utian, W. H. Effect of postmenopausal estrogen therapy on diastolic blood pressure and bodyweight. Maturitas 1, 3–8 (1978).

    Article  CAS  PubMed  Google Scholar 

  78. Lip, G. Y., Beevers, M., Churchill, D. & Beevers, D. G. Hormone replacement therapy and blood pressure in hypertensive women. J. Hum. Hypertens. 8, 491–494 (1994).

    CAS  PubMed  Google Scholar 

  79. Pripp, U. et al. A randomized trial on effects of hormone therapy on ambulatory blood pressure and lipoprotein levels in women with coronary artery disease. J. Hypertens. 17, 1379–1386 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Schunkert, H. et al. Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. Circulation 95, 39–45 (1997).

    Article  CAS  PubMed  Google Scholar 

  81. Ashraf, M. S. & Vongpatanasin, W. Estrogen and hypertension. Curr. Hypertens. Rep. 8, 368–376 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Hinojosa-Laborde, C. et al. Ovariectomy augments hypertension in aging female Dahl salt-sensitive rats. Hypertension 44, 405–409 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Sampson, A. K. et al. The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent. Am.J. Physiol. Regul. Integr. Comp. Physiol. 302, R159–R165 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Brosnihan, K. B., Li, P., Ganten, D. & Ferrario, C. M. Estrogen protects transgenic hypertensive rats by shifting the vasoconstrictor-vasodilator balance of RAS. Am. J. Physiol. 273, R1908–R1915 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Cherney, A., Edgell, H. & Krukoff, T. L. NO mediates effects of estrogen on central regulation of blood pressure in restrained, ovariectomized rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R842–R849 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Ojeda, N. B., Grigore, D., Robertson, E. B. & Alexander, B. T. Estrogen protects against increased blood pressure in postpubertal female growth restricted offspring. Hypertension 50, 679–685 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Lam, K. K., Hu, C. T., Ou, T. Y., Yen, M. H. & Chen, H. I. Effects of oestrogen replacement on steady and pulsatile haemodynamics in ovariectomized rats. Br. J. Pharmacol. 136, 811–818 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Reckelhoff, J. F., Zhang, H. & Granger, J. P. Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats. Hypertension 31, 435–439 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Denton, K.,M., Kett, M. M. & Dodic, M. in Early Life Origins of Health and Disease (eds Wintour-Coghlan, E. M. & Owens, J. A.) 103–129 (Springer, 2006).

    Book  Google Scholar 

  90. Hernandez, I. et al. 17β-estradiol prevents oxidative stress and decreases blood pressure in ovariectomized rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R1599–R1605 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Farhat, M. Y., Lavigne, M. C. & Ramwell, P. W. The vascular protective effects of estrogen. FASEB J. 10, 615–624 (1996).

    Article  CAS  PubMed  Google Scholar 

  92. Mendelsohn, M. E. & Karas, R. H. The protective effects of estrogen on the cardiovascular system. N. Engl. J. Med. 340, 1801–1811 (1999).

    Article  CAS  PubMed  Google Scholar 

  93. Pasqualini, C., Leviel, V., Guibert, B., Faucon-Biguet, N. & Kerdelhue, B. Inhibitory actions of acute estradiol treatment on the activity and quantity of tyrosine hydroxylase in the median eminence of ovariectomized rats. J. Neuroendocrinol. 3, 575–580 (1991).

    Article  CAS  PubMed  Google Scholar 

  94. Ylikorkala, O., Orpana, A., Puolakka, J., Pyorala, T. & Viinikka, L. Postmenopausal hormonal replacement decreases plasma levels of endothelin-1. J. Clin. Endocrinol. Metab. 80, 3384–3387 (1995).

    CAS  PubMed  Google Scholar 

  95. Klett, C. et al. Regulation of hepatic angiotensinogen synthesis and secretion by steroid hormones. Endocrinology 130, 3660–3668 (1992).

    Article  CAS  PubMed  Google Scholar 

  96. Brosnihan, K. B., Hodgin, J. B., 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-α knock-out mice. Exp. Physiol. 93, 658–664 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Seltzer, A. et al. Estrogens regulate angiotensin-converting enzyme and angiotensin receptors in female rat anterior pituitary. Neuroendocrinology 55, 460–467 (1992).

    Article  CAS  PubMed  Google Scholar 

  98. Ozono, R. et al. Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney. Hypertension 30, 1238–1246 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Miyata, N., Park, F., Li, X. F. & Cowley, A. W. Jr. Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney. Am. J. Physiol. 277, F437–F446 (1999).

    CAS  PubMed  Google Scholar 

  100. Baiardi, G. et al. Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat. Regul. Pept. 124, 7–17 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Sampson, A. K., Moritz, K. M. & Denton, K. M. Postnatal ontogeny of angiotensin receptors and ACE2 in male and female rats. Gend. Med. 9, 21–32 (2012).

    Article  PubMed  Google Scholar 

  102. Roesch, D. M. et al. Estradiol attenuates angiotensin-induced aldosterone secretion in ovariectomized rats. Endocrinology 141, 4629–4636 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. Nickenig, G. et al. Differential effects of estrogen and progesterone on AT(1) receptor gene expression in vascular smooth muscle cells. Circulation 102, 1828–1833 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Akishita, M. et al. Estrogen attenuates endothelin-1 production by bovine endothelial cells via estrogen receptor. Biochem. Biophys. Res. Commun. 251, 17–21 (1998).

    Article  CAS  PubMed  Google Scholar 

  105. Akishita, M. et al. Estrogen inhibits endothelin-1 production and c-fos gene expression in rat aorta. Atherosclerosis 125, 27–38 (1996).

    Article  CAS  PubMed  Google Scholar 

  106. Dubey, R. K., Jackson, E. K., Keller, P. J., Imthurn, B. & Rosselli, M. Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanism. Hypertension 37, 640–644 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Hong, H. J. et al. 17β-estradiol downregulates angiotensin-II-induced endothelin-1 gene expression in rat aortic smooth muscle cells. J. Biomed. Sci. 11, 27–36 (2004).

    CAS  PubMed  Google Scholar 

  108. Chao, H. H. et al. Inhibition of angiotensin II induced endothelin-1 gene expression by 17-β-oestradiol in rat cardiac fibroblasts. Heart 91, 664–669 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bilsel, A. S. et al. 17β-estradiol modulates endothelin-1 expression and release in human endothelial cells. Cardiovasc. Res. 46, 579–584 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Tan, Z., Wang, T. H., Yang, D., Fu, X. D. & Pan, J. Y. Mechanisms of 17β-estradiol on the production of ET-1 in ovariectomized rats. Life Sci. 73, 2665–2674 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Rodrigo, M. C., Martin, D. S. & Eyster, K. M. Vascular ECE-1 mRNA expression decreases in response to estrogens. Life Sci. 73, 2973–2983 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Barber, D. A., Michener, S. R., Ziesmer, S. C. & Miller, V. M. Chronic increases in blood flow upregulate endothelin-B receptors in arterial smooth muscle. Am. J. Physiol. 270, H65–H71 (1996).

    CAS  PubMed  Google Scholar 

  113. Nuedling, S. et al. 17β-estradiol regulates the expression of endothelin receptor type B in the heart. Br. J. Pharmacol. 140, 195–201 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Penna, C. et al. Effect of endothelins on the cardiovascular system. J. Cardiovasc. Med. (Hagerstown) 7, 645–652 (2006).

    Article  Google Scholar 

  115. David, F. L. et al. Ovarian hormones modulate endothelin-1 vascular reactivity and mRNA expression in DOCA-salt hypertensive rats. Hypertension 38, 692–696 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Gohar, E. Y., Yusuf, C. & Pollock, D. M. Ovarian hormones modulate endothelin A and B receptor expression. Life Sci. 159, 148–152 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tostes, R. C. et al. Endothelin, sex and hypertension. Clin. Sci. 114, 85–97 (2008).

    Article  CAS  Google Scholar 

  118. Nakano, D. & Pollock, D. M. Contribution of endothelin A receptors in endothelin 1-dependent natriuresis in female rats. Hypertension 53, 324–330 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Nakano, D., Pollock, J. S. & Pollock, D. M. Renal medullary ETB receptors produce diuresis and natriuresis via NOS1. Am. J. Physiol. Renal Physiol. 294, F1205–F1211 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Dunne, F. P., Barry, D. G., Ferriss, J. B., Grealy, G. & Murphy, D. Changes in blood pressure during the normal menstrual cycle. Clin. Sci. 81, 515–518 (1991).

    Article  CAS  Google Scholar 

  121. Hayashi, K. et al. Variations in carotid arterial compliance during the menstrual cycle in young women. Exp. Physiol. 91, 465–472 (2006).

    Article  PubMed  Google Scholar 

  122. Chapman, A. B. et al. Systemic and renal hemodynamic changes in the luteal phase of the menstrual cycle mimic early pregnancy. Am. J. Physiol. 273, F777–F782 (1997).

    CAS  PubMed  Google Scholar 

  123. Williams, M. R. et al. Variations in endothelial function and arterial compliance during the menstrual cycle. J. Clin. Endocrinol. Metab. 86, 5389–5395 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Polderman, K. H. et al. Influence of sex hormones on plasma endothelin levels. Ann. Intern. Med. 118, 429–432 (1993).

    Article  CAS  PubMed  Google Scholar 

  125. Kittikulsuth, W., Sullivan, J. C. & Pollock, D. M. ET-1 actions in the kidney: evidence for sex differences. Br. J. Pharmacol. 168, 318–326 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hilliard, L. M. et al. Gender differences in pressure-natriuresis and renal autoregulation: role of the angiotensin type 2 receptor. Hypertension 57, 275–282 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Gant, N. F., Daley, G. L., Chand, S., Whalley, P. J. & MacDonald, P. C. A study of angiotensin II pressor response throughout primigravid pregnancy. J. Clin. Invest. 52, 2682–2689 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Saijo, Y. et al. Altered sensitivity to a novel vasoconstrictor endothelin-1 (1–31) in myometrium and umbilical artery of women with severe preeclampsia. Biochem. Biophys. Res. Commun. 286, 964–967 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Polderman, K. H., Stehouwer, C. D., van Kamp, G. J., Schalkwijk, C. G. & Gooren, L. J. Modulation of plasma endothelin levels by the menstrual cycle. Metabolism 49, 648–650 (2000).

    Article  CAS  PubMed  Google Scholar 

  130. Rossouw, J. E. 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 288, 321–333 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Dubey, R. K., Imthurn, B., Barton, M. & Jackson, E. K. Vascular consequences of menopause and hormone therapy: importance of timing of treatment and type of estrogen. Cardiovasc. Res. 66, 295–306 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Miller, V. M. & Harman, S. M. An update on hormone therapy in postmenopausal women: mini-review for the basic scientist. Am. J. Physiol. Heart Circ. Physiol. 313, H1013–H1021 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Schierbeck, L. L. et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 345, e6409 (2012).

    Article  PubMed  CAS  Google Scholar 

  134. Schierbeck, L. L., Kober, L. & Jensen, J. E. Authors' reply to Marjorbanks and collegues, Rossouw and collegues, Schroll and Lundh, and McPherson. Br. Med. J. 345, e8164 (2012).

    Article  CAS  Google Scholar 

  135. Muka, T. et al. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis. JAMA Cardiol. 1, 767–776 (2016).

    Article  PubMed  Google Scholar 

  136. Manson, J. E. et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women's Health Initiative randomized trials. JAMA 318, 927–938 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Cooke, P. S., Nanjappa, M. K., Ko, C., Prins, G. S. & Hess, R. A. Estrogens in male physiology. Physiol. Rev. 97, 995–1043 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Jones, M. E. et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc. Natl Acad. Sci. USA 97, 12735–12740 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Van Sinderen, M. et al. Sexual dimorphism in the glucose homeostasis phenotype of the aromatase knockout (ArKO) mice. J. Steroid Biochem. Mol. Biol. 170, 39–48 (2017).

    Article  CAS  PubMed  Google Scholar 

  140. Kovats, S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell. Immunol. 294, 63–69 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Popkov, V. A. et al. Diseases and aging: gender matters. Biochem. (Mosc) 80, 1560–1570 (2015).

    Article  CAS  Google Scholar 

  142. Salton, C. J. et al. Gender differences and normal left ventricular anatomy in an adult population free of hypertension. A cardiovascular magnetic resonance study of the Framingham Heart Study Offspring cohort. J. Am. Coll. Cardiol. 39, 1055–1060 (2002).

    Article  PubMed  Google Scholar 

  143. Sampson, A. K., Jennings, G. L. & Chin-Dusting, J. P. Y are males so difficult to understand?: a case where “X” does not mark the spot. Hypertension 59, 525–531 (2012).

    Article  CAS  PubMed  Google Scholar 

  144. Sullivan, J. C. Sex and the renin-angiotensin system: inequality between the sexes in response to RAS stimulation and inhibition. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1220–R1226 (2008).

    Article  CAS  PubMed  Google Scholar 

  145. Silva-Antonialli, M. M. et al. A lower ratio of AT1/AT2 receptors of angiotensin II is found in female than in male spontaneously hypertensive rats. Cardiovasc. Res. 62, 587–593 (2004).

    Article  CAS  PubMed  Google Scholar 

  146. Sandberg, K. & Ji, H. Sex differences in primary hypertension. Biol. Sex. Differ. 3, 7 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Sainz, J. et al. Role of sex, gonadectomy and sex hormones in the development of nitric oxide inhibition-induced hypertension. Exp. Physiol. 89, 155–162 (2004).

    Article  CAS  PubMed  Google Scholar 

  148. Kittikulsuth, W., Looney, S. W. & Pollock, D. M. Endothelin ET(B) receptors contribute to sex differences in blood pressure elevation in angiotensin II hypertensive rats on a high-salt diet. Clin. Exp. Pharmacol. Physiol. 40, 362–370 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Quan, A. et al. Androgens augment proximal tubule transport. Am. J. Physiol. Renal Physiol. 287, F452–F459 (2004).

    Article  CAS  PubMed  Google Scholar 

  150. Liu, B. & Ely, D. Testosterone increases: sodium reabsorption, blood pressure, and renal pathology in female spontaneously hypertensive rats on a high sodium diet. Adv. Pharmacol. Sci. 2011, 817835 (2011).

    PubMed  PubMed Central  Google Scholar 

  151. van Kesteren, P. J. et al. The effects of sex steroids on plasma levels of marker proteins of endothelial cell functioning. Thromb. Haemost. 79, 1029–1033 (1998).

    Article  CAS  PubMed  Google Scholar 

  152. Kellogg, D. L. Jr, Liu, Y. & Pergola, P. E. Selected contribution: gender differences in the endothelin-B receptor contribution to basal cutaneous vascular tone in humans. J. Appl. Physiol. 91, 2407–2411 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. Corona, G. et al. Testosterone supplementation and body composition: results from a meta-analysis of observational studies. J. Endocrinol. Invest. 39, 967–981 (2016).

    Article  CAS  PubMed  Google Scholar 

  154. Traish, A. M. Testosterone therapy in men with testosterone deficiency: are the benefits and cardiovascular risks real or imagined? Am. J. Physiol. Regul. Integr. Comp. Physiol. 311, R566–R573 (2016).

    Article  PubMed  Google Scholar 

  155. Burt Solorzano, C. M. et al. Neuroendocrine dysfunction in polycystic ovary syndrome. Steroids 77, 332–337 (2012).

    Article  CAS  PubMed  Google Scholar 

  156. Colafella, K. M., Hilliard, L. M. & Denton, K. M. Epochs in the depressor/pressor balance of the renin-angiotensin system. Clin. Sci. 130, 761–771 (2016).

    Article  CAS  Google Scholar 

  157. Leblanc, S. et al. Angiotensin II type 2 receptor stimulation improves fatty acid ovarian uptake and hyperandrogenemia in an obese rat model of polycystic ovary syndrome. Endocrinology 155, 3684–3693 (2014).

    Article  PubMed  CAS  Google Scholar 

  158. Pucell, A. G., Hodges, J. C., Sen, I., Bumpus, F. M. & Husain, A. Biochemical properties of the ovarian granulosa cell type 2-angiotensin II receptor. Endocrinology 128, 1947–1959 (1991).

    Article  CAS  PubMed  Google Scholar 

  159. Yoshimura, Y. et al. Angiotensin II induces ovulation and oocyte maturation in rabbit ovaries via the AT2 receptor subtype. Endocrinology 137, 1204–1211 (1996).

    Article  CAS  PubMed  Google Scholar 

  160. Bani, D. Relaxin as a natural agent for vascular health. Vasc. Health Risk Manag. 4, 515–524 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Samuel, C. S. et al. Anti-fibrotic actions of relaxin. Br. J. Pharmacol. 174, 962–976 (2017).

    Article  CAS  PubMed  Google Scholar 

  162. Mirabito Colafella, K. M., Samuel, C. S. & Denton, K. M. Relaxin contributes to the regulation of arterial pressure in adult female mice. Clin. Sci. 131, 2795–2805 (2017).

    Article  CAS  Google Scholar 

  163. dos Santos, R. L., da Silva, F. B., Ribeiro, R. F. Jr & Stefanon, I. Sex hormones in the cardiovascular system. Horm. Mol. Biol. Clin. Investig. 18, 89–103 (2014).

    PubMed  Google Scholar 

  164. Wenner, M. M. & Stachenfeld, N. S. Blood pressure and water regulation: understanding sex hormone effects within and between men and women. J. Physiol. 590, 5949–5961 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Petersson, M. Cardiovascular effects of oxytocin. Prog. Brain Res. 139, 281–288 (2002).

    Article  CAS  PubMed  Google Scholar 

  166. Petersson, M., Lundeberg, T. & Uvnas-Moberg, K. Oxytocin decreases blood pressure in male but not in female spontaneously hypertensive rats. J. Auton. Nerv. Syst. 66, 15–18 (1997).

    Article  CAS  PubMed  Google Scholar 

  167. Vargas-Martinez, F. et al. Oxytocin, a main breastfeeding hormone, prevents hypertension acquired in utero: a therapeutics preview. Biochim. Biophys. Acta 1861, 3071–3084 (2017).

    Article  CAS  Google Scholar 

  168. Georgiopoulos, G. et al. Prolactin as a predictor of endothelial dysfunction and arterial stiffness progression in menopause. J. Hum. Hypertens. 31, 520–524 (2017).

    Article  CAS  PubMed  Google Scholar 

  169. Tamma, G., Goswami, N., Reichmuth, J., De Santo, N. G. & Valenti, G. Aquaporins, vasopressin, and aging: current perspectives. Endocrinology 156, 777–788 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Stachenfeld, N. S., Splenser, A. E., Calzone, W. L., Taylor, M. P. & Keefe, D. L. Sex differences in osmotic regulation of AVP and renal sodium handling. J. Appl. Physiol. 91, 1893–1901 (2001) (1985).

    Article  CAS  PubMed  Google Scholar 

  171. Wang, Y. X., Crofton, J. T. & Share, L. Sex differences in the cardiovascular and renal actions of vasopressin in conscious rats. Am. J. Physiol. 272, R370–R376 (1997).

    CAS  PubMed  Google Scholar 

  172. Denton, K. M. “You are what you drink!” Focus on “Rehydration with soft drink-like beverages exacerbates dehydration and worsens dehydration-associated renal injury”. Am. J. Physiol. Regul. Integr. Comp. Physiol. 311, R12–R13 (2016).

    Article  PubMed  Google Scholar 

  173. Arnold, A. P., Cassis, L. A., Eghbali, M., Reue, K. & Sandberg, K. Sex hormones and sex chromosomes cause sex differences in the development of cardiovascular diseases. Arterioscler Thromb. Vasc. Biol. 37, 746–756 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Balaton, B. P. & Brown, C. J. Escape artists of the X chromosome. Trends Genet. 32, 348–359 (2016).

    Article  CAS  PubMed  Google Scholar 

  175. Arnold, A. P. et al. The importance of having two X chromosomes. Phil. Trans. R. Soc. B 371, 20150113 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  176. Xu, J. & Andreassi, M. Reversible histone methylation regulates brain gene expression and behavior. Horm. Behav. 59, 383–392 (2011).

    Article  CAS  PubMed  Google Scholar 

  177. Wijchers, P. J. & Festenstein, R. J. Epigenetic regulation of autosomal gene expression by sex chromosomes. Trends Genet. 27, 132–140 (2011).

    Article  CAS  PubMed  Google Scholar 

  178. Manwani, B. et al. Sex differences in ischemic stroke sensitivity are influenced by gonadal hormones, not by sex chromosome complement. J. Cereb. Blood Flow Metab. 35, 221–229 (2015).

    Article  CAS  PubMed  Google Scholar 

  179. Ji, H. et al. Sex chromosome effects unmasked in angiotensin II-induced hypertension. Hypertension 55, 1275–1282 (2010).

    Article  CAS  PubMed  Google Scholar 

  180. Alsiraj, Y. et al. Female mice with an XY sex chromosome complement develop severe angiotensin II-induced abdominal aortic aneurysms. Circulation 135, 379–391 (2017).

    Article  CAS  PubMed  Google Scholar 

  181. Li, J. et al. The number of X chromosomes influences protection from cardiac ischaemia/reperfusion injury in mice: one X is better than two. Cardiovasc. Res. 102, 375–384 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Link, J. C. et al. Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes. Arterioscler Thromb. Vasc. Biol. 35, 1778–1786 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Chen, X. et al. The number of x chromosomes causes sex differences in adiposity in mice. PLOS Genet. 8, e1002709 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Ahmed, B. et al. Diabetes mellitus, hypothalamic hypoestrogenemia, and coronary artery disease in premenopausal women (from the National Heart, Lung, and Blood Institute sponsored WISE study). Am. J. Cardiol. 102, 150–154 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Mavinkurve, M. & O'Gorman, C. S. Cardiometabolic and vascular risks in young and adolescent girls with Turner syndrome. BBA Clin. 3, 304–309 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Calogero, A. E. et al. Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders. J. Endocrinol. Invest. 40, 705–712 (2017).

    Article  CAS  PubMed  Google Scholar 

  187. Winkler, T. W. et al. The influence of age and sex on genetic associations with adult body size and shape: a large-scale genome-wide interaction study. PLOS Genet. 11, e1005378 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Huby, R. D., Glaves, P. & Jackson, R. The incidence of sexually dimorphic gene expression varies greatly between tissues in the rat. PLOS One 9, e115792 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Kwekel, J. C., Desai, V. G., Moland, C. L., Vijay, V. & Fuscoe, J. C. Life cycle analysis of kidney gene expression in male F344 rats. PLOS One 8, e75305 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. McDonough, A. A. & Nguyen, M. T. Maintaining balance under pressure: integrated regulation of renal transporters during hypertension. Hypertension 66, 450–455 (2015).

    Article  CAS  PubMed  Google Scholar 

  191. Kwekel, J. C. et al. Sex and age differences in the expression of liver microRNAs during the life span of F344 rats. Biol. Sex. Differ. 8, 6 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Milsted, A. et al. Regulation of tyrosine hydroxylase gene transcription by Sry. Neurosci. Lett. 369, 203–207 (2004).

    Article  CAS  PubMed  Google Scholar 

  193. Ely, D. et al. Spontaneously hypertensive rat Y chromosome increases indexes of sympathetic nervous system activity. Hypertension 29, 613–618 (1997).

    Article  CAS  PubMed  Google Scholar 

  194. Araujo, F. C. et al. Similarities and differences of X and Y chromosome homologous genes, SRY and SOX3, in regulating the renin-angiotensin system promoters. Physiol. Genom. 47, 177–186 (2015).

    Article  CAS  Google Scholar 

  195. Milsted, A. et al. Regulation of multiple renin-angiotensin system genes by Sry. J. Hypertens. 28, 59–64 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Reckelhoff, J. F., Zhang, H., Srivastava, K. & Granger, J. P. Gender differences in hypertension in spontaneously hypertensive rats: role of androgens and androgen receptor. Hypertension 34, 920–923 (1999).

    Article  CAS  PubMed  Google Scholar 

  197. Li, Y., Zhu, M., Hu, R. & Yan, W. The effects of gene polymorphisms in angiotensin II receptors on pregnancy-induced hypertension and preeclampsia: a systematic review and meta-analysis. Hypertens. Pregnancy 34, 241–260 (2015).

    Article  CAS  PubMed  Google Scholar 

  198. Tousoulis, D. et al. Genetic polymorphism on type 2 receptor of angiotensin II, modifies cardiovascular risk and systemic inflammation in hypertensive males. Am. J. Hypertens. 23, 237–242 (2010).

    Article  CAS  PubMed  Google Scholar 

  199. Spolarics, Z. The X-files of inflammation: cellular mosaicism of X-linked polymorphic genes and the female advantage in the host response to injury and infection. Shock 27, 597–604 (2007).

    Article  CAS  PubMed  Google Scholar 

  200. Guzik, T. J. et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J. Exp. Med. 204, 2449–2460 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Ji, H. et al. Sex-specific T-cell regulation of angiotensin II-dependent hypertension. Hypertension 64, 573–582 (2014).

    Article  CAS  PubMed  Google Scholar 

  202. Pollow, D. P. et al. Sex differences in T-lymphocyte tissue infiltration and development of angiotensin II hypertension. Hypertension 64, 384–390 (2014).

    Article  CAS  PubMed  Google Scholar 

  203. Zimmerman, M. A., Baban, B., Tipton, A. J., O'Connor, P. M. & Sullivan, J. C. Chronic ANG II infusion induces sex-specific increases in renal T cells in Sprague-Dawley rats. Am. J. Physiol. Renal Physiol. 308, F706–712 (2015).

    Article  CAS  PubMed  Google Scholar 

  204. Tipton, A. J., Baban, B. & Sullivan, J. C. Female spontaneously hypertensive rats have greater renal anti-inflammatory T lymphocyte infiltration than males. Am. J. Physiol. Regul. Integr. Comp. Physiol. 303, R359–367 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Amadori, A. et al. Genetic control of the CD4/CD8 T-cell ratio in humans. Nat. Med. 1, 1279–1283 (1995).

    Article  CAS  PubMed  Google Scholar 

  206. Zhang, M. A. et al. Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way. Proc. Natl Acad. Sci. USA 109, 9505–9510 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Tedeschi, S. K., Bermas, B. & Costenbader, K. H. Sexual disparities in the incidence and course of SLE and RA. Clin. Immunol. 149, 211–218 (2013).

    Article  CAS  PubMed  Google Scholar 

  208. Yang, J. et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 60, 1472–1483 (2009).

    Article  PubMed  Google Scholar 

  209. Lee, H. Y. et al. Altered frequency and migration capacity of CD4+CD25+ regulatory T cells in systemic lupus erythematosus. Rheumatology 47, 789–794 (2008).

    Article  CAS  PubMed  Google Scholar 

  210. Ryan, M. J. The pathophysiology of hypertension in systemic lupus erythematosus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R1258–R1267 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Wallace, K. et al. CD4+ T cells are important mediators of oxidative stress that cause hypertension in response to placental ischemia. Hypertension 64, 1151–1158 (2014).

    Article  CAS  PubMed  Google Scholar 

  212. Cornelius, D. C. & Lamarca, B. TH17- and IL-17- mediated autoantibodies and placental oxidative stress play a role in the pathophysiology of pre-eclampsia. Minerva Ginecol. 66, 243–249 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Cao, X., Wang, L. L. & Luo, X. Expression of regulatory T and helper T cells in peripheral blood of patients with pregnancy-induced hypertension. Clin. Exp. Obstet. Gynecol. 40, 502–504 (2013).

    CAS  PubMed  Google Scholar 

  214. Pepe, G. et al. Self-renewal and phenotypic conversion are the main physiological responses of macrophages to the endogenous estrogen surge. Sci. Rep. 7, 44270 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Mozaffarian, D. et al. Heart disease and stroke statistics — 2016 update: a report from the American Heart Association. Circulation 133, e38–e360 (2016).

    PubMed  Google Scholar 

  216. Appelman, Y., van Rijn, B. B., Ten Haaf, M. E., Boersma, E. & Peters, S. A. Sex differences in cardiovascular risk factors and disease prevention. Atherosclerosis 241, 211–218 (2015).

    Article  CAS  PubMed  Google Scholar 

  217. Flegal, K. M. Body-mass index and all-cause mortality. Lancet 389, 2284–2285 (2017).

    Article  PubMed  Google Scholar 

  218. Walker, R. K. et al. The good, the bad, and the ugly with alcohol use and abuse on the heart. Alcohol Clin. Exp. Res. 37, 1253–1260 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Zheng, Y. L. et al. Alcohol intake and associated risk of major cardiovascular outcomes in women compared with men: a systematic review and meta-analysis of prospective observational studies. BMC Publ. Health 15, 773 (2015).

    Article  CAS  Google Scholar 

  220. Bell, S. et al. Association between clinically recorded alcohol consumption and initial presentation of 12 cardiovascular diseases: population based cohort study using linked health records. BMJ 356, j909 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  221. Huxley, R. R. & Woodward, M. Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies. Lancet 378, 1297–1305 (2011).

    Article  PubMed  Google Scholar 

  222. Peters, S. A., Huxley, R. R. & Woodward, M. Smoking as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 81 cohorts, including 3,980,359 individuals and 42,401 strokes. Stroke 44, 2821–2828 (2013).

    Article  PubMed  Google Scholar 

  223. Zhao, J., Leung, J. Y., Lin, S. L. & Schooling, C. M. Cigarette smoking and testosterone in men and women: A systematic review and meta-analysis of observational studies. Prev. Med. 85, 1–10 (2016).

    Article  PubMed  Google Scholar 

  224. Baron, J. A., La Vecchia, C. & Levi, F. The antiestrogenic effect of cigarette smoking in women. Am. J. Obstet. Gynecol. 162, 502–514 (1990).

    Article  CAS  PubMed  Google Scholar 

  225. Flegal, K. M., Carroll, M. D., Ogden, C. L. & Curtin, L. R. Prevalence and trends in obesity among US adults, 1999–2008. JAMA 303, 235–241 (2010).

    Article  CAS  PubMed  Google Scholar 

  226. Kajiwara, A. et al. Sex differences in the renal function decline of patients with type 2 diabetes. J. Diabetes Res. 2016, 4626382 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  227. Wilson, P. W., D'Agostino, R. B., Sullivan, L., Parise, H. & Kannel, W. B. Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch. Intern. Med. 162, 1867–1872 (2002).

    Article  PubMed  Google Scholar 

  228. Wilmot, K. A., O'Flaherty, M., Capewell, S., Ford, E. S. & Vaccarino, V. Coronary heart disease mortality declines in the United States from 1979 through 2011: evidence for stagnation in young adults, especially women. Circulation 132, 997–1002 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Collaboration, N. C. D. R. F. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet 387, 1377–1396 (2016).

    Article  Google Scholar 

  230. Towfighi, A., Zheng, L. & Ovbiagele, B. Weight of the obesity epidemic: rising stroke rates among middle-aged women in the United States. Stroke 41, 1371–1375 (2010).

    Article  PubMed  Google Scholar 

  231. Wilsgaard, T., Schirmer, H. & Arnesen, E. Impact of body weight on blood pressure with a focus on sex differences: the Tromso Study, 1986–1995. Arch. Intern. Med. 160, 2847–2853 (2000).

    Article  CAS  PubMed  Google Scholar 

  232. Fried, S. K., Lee, M. J. & Karastergiou, K. Shaping fat distribution: New insights into the molecular determinants of depot- and sex-dependent adipose biology. Obesity (Silver Spring) 23, 1345–1352 (2015).

    Article  CAS  Google Scholar 

  233. Hellstrom, L., Wahrenberg, H., Hruska, K., Reynisdottir, S. & Arner, P. Mechanisms behind gender differences in circulating leptin levels. J. Intern. Med. 247, 457–462 (2000).

    Article  CAS  PubMed  Google Scholar 

  234. Lambert, E. et al. Gender differences in sympathetic nervous activity: influence of body mass and blood pressure. J. Hypertens. 25, 1411–1419 (2007).

    Article  CAS  PubMed  Google Scholar 

  235. Huby, A. C. et al. Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis. Circulation 132, 2134–2145 (2015).

    Article  CAS  PubMed  Google Scholar 

  236. Huby, A. C., Otvos, L. Jr & Belin de Chantemele, E. J. Leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in obese female mice. Hypertension 67, 1020–1028 (2016).

    Article  CAS  PubMed  Google Scholar 

  237. Calhoun, D. A. & Sharma, K. The role of aldosteronism in causing obesity-related cardiovascular risk. Cardiol. Clin. 28, 517–527 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Dumeige, L. et al. Sex-specificity of mineralocorticoid target gene expression during renal development, and long-term consequences. Int. J. Mol. Sci. 18, 457 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  239. Wang, Y. et al. Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice. Am. J. Physiol. Heart Circ. Physiol. 312, H459–H468 (2017).

    Article  PubMed  Google Scholar 

  240. Wang, Y. et al. Administration of 17β-estradiol to ovariectomized obese female mice reverses obesity-hypertension through an ACE2-dependent mechanism. Am. J. Physiol. Endocrinol. Metab. 308, E1066–1075 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  241. Putnam, K., Shoemaker, R., Yiannikouris, F. & Cassis, L. A. The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome. Am. J. Physiol. Heart Circ. Physiol. 302, H1219–H1230 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Valencak, T. G., Osterrieder, A. & Schulz, T. J. Sex matters: The effects of biological sex on adipose tissue biology and energy metabolism. Redox Biol. 12, 806–813 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Nichols, M. et al. European Cardiovascular Disease Statistics 2012 (European Heart Network/European Society of Cardiology, 2012).

  244. Pedersen, L. R. et al. Risk factors for myocardial infarction in women and men: a review of the current literature. Curr. Pharm. Des. 22, 3835–3852 (2016).

    Article  CAS  PubMed  Google Scholar 

  245. O'Donovan, G., Kearney, E., Sherwood, R. & Hillsdon, M. Fatness, fitness, and cardiometabolic risk factors in middle-aged white men. Metabolism 61, 213–220 (2012).

    Article  CAS  PubMed  Google Scholar 

  246. Straface, E., Gambardella, L., Brandani, M. & Malorni, W. in Sex and Gender Differences in Pharmacology (ed. Regitz-Zagrosek, V.) 49–65 (Springer, 2012).

    Google Scholar 

  247. Kwok, M. K., Au Yeung, S. L., Leung, G. M. & Schooling, C. M. Birth weight, infant growth, and adolescent blood pressure using twin status as an instrumental variable in a Chinese birth cohort: “Children of 1997”. Ann. Epidemiol. 24, 509–515 (2014).

    Article  PubMed  Google Scholar 

  248. Williams, S. & Poulton, R. Birth size, growth, and blood pressure between the ages of 7 and 26 years: failure to support the fetal origins hypothesis. Am. J. Epidemiol. 155, 849–852 (2002).

    Article  PubMed  Google Scholar 

  249. Roberts, J. & Maurer, K. Blood pressure of youths 12–17 years: United States. Vital Health Stat 11, iii–vi, 1–62 (1977).

    Google Scholar 

  250. Drizd, T., Dannenberg, A. L. & Engel, A. Blood pressure levels in persons 18–74 years of age in 1976–1980, and trends in blood pressure from 1960 to 1980 in the United States. Vital Health Stat. 11, 1–68 (1986).

    Google Scholar 

  251. Boynton, R. E. & Todd, R. L. Blood pressure readings of 75,258 university students. Arch. Intern. Med. 80, 454–462 (1947).

    Article  CAS  Google Scholar 

  252. Fernandez-Atucha, A. et al. Sex differences in the aging pattern of renin-angiotensin system serum peptidases. Biol. Sex. Differ. 8, 5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Collaboration, N. C. D. R. F. Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants. Lancet 389, 37–55 (2017).

    Article  Google Scholar 

  254. Masubuchi, Y., Kumai, T., Uematsu, A., Komoriyama, K. & Hirai, M. Gonadectomy-induced reduction of blood pressure in adult spontaneously hypertensive rats. Acta Endocrinol. 101, 154–160 (1982).

    Article  CAS  Google Scholar 

  255. Iams, S. G., McMurthy, J. P. & Wexler, B. C. Aldosterone, deoxycorticosterone, corticosterone, and prolactin changes during the lifespan of chronically and spontaneously hypertensive rats. Endocrinology 104, 1357–1363 (1979).

    Article  CAS  PubMed  Google Scholar 

  256. Chen, Y. F. & Meng, Q. C. Sexual dimorphism of blood pressure in spontaneously hypertensive rats is androgen dependent. Life Sci. 48, 85–96 (1991).

    Article  CAS  PubMed  Google Scholar 

  257. Sullivan, J. C., Semprun-Prieto, L., Boesen, E. I., Pollock, D. M. & Pollock, J. S. Sex and sex hormones influence the development of albuminuria and renal macrophage infiltration in spontaneously hypertensive rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1573–R1579 (2007).

    Article  CAS  PubMed  Google Scholar 

  258. Sullivan, J. C., Sasser, J. M. & Pollock, J. S. Sexual dimorphism in oxidant status in spontaneously hypertensive rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R764–R768 (2007).

    Article  CAS  PubMed  Google Scholar 

  259. Sullivan, J. C., Bhatia, K., Yamamoto, T. & Elmarakby, A. A. Angiotensin (1–7) receptor antagonism equalizes angiotensin II-induced hypertension in male and female spontaneously hypertensive rats. Hypertension 56, 658–666 (2010).

    Article  CAS  PubMed  Google Scholar 

  260. Bhatia, K., Elmarakby, A. A., El-Remessy, A. B. & Sullivan, J. C. Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R274–R282 (2012).

    Article  CAS  PubMed  Google Scholar 

  261. Elmarakby, A. A., Bhatia, K., Crislip, R. & Sullivan, J. C. Hemodynamic responses to acute angiotensin II infusion are exacerbated in male versus female spontaneously hypertensive rats. Physiol. Rep. 4, e12677 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  262. Fortepiani, L. A. et al. Characterization of an animal model of postmenopausal hypertension in spontaneously hypertensive rats. Hypertension 41, 640–645 (2003).

    Article  CAS  PubMed  Google Scholar 

  263. Davidson, A. O. et al. Blood pressure in genetically hypertensive rats. Influence of the Y chromosome. Hypertension 26, 452–459 (1995).

    Article  CAS  PubMed  Google Scholar 

  264. Crofton, J. T., Ota, M. & Share, L. Role of vasopressin, the renin-angiotensin system and sex in Dahl salt-sensitive hypertension. J. Hypertens. 11, 1031–1038 (1993).

    Article  CAS  PubMed  Google Scholar 

  265. Rowland, N. E. & Fregly, M. J. Role of gonadal hormones in hypertension in the Dahl salt-sensitive rat. Clin. Exp. Hypertens. A 14, 367–375 (1992).

    CAS  PubMed  Google Scholar 

  266. Ashton, N. & Balment, R. J. Sexual dimorphism in renal function and hormonal status of New Zealand genetically hypertensive rats. Acta Endocrinol. 124, 91–97 (1991).

    Article  CAS  Google Scholar 

  267. Fentie, I. H., Greenwood, M. M., Wyss, J. M. & Clark, J. T. Age-related decreases in gonadal hormones in Long-Evans rats: relationship to rise in arterial pressure. Endocr 25, 15–22 (2004).

    Article  CAS  Google Scholar 

  268. Van Liere, E. J., Stickney, J. C. & Marsh, D. F. Sex differences in blood pressure of dogs. Science 109, 489 (1949).

    Article  CAS  PubMed  Google Scholar 

  269. Evans, R. G. et al. Sex differences in pressure diuresis/natriuresis in rabbits. Acta Physiol. Scand. 169, 309–316 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

K.M.M.C is supported by an Australian National Health and Medical Research Council (NHMRC) CJ Martin Research Fellowship (1112125), and K.M.D is supported by an NHMRC Senior Research Fellowship (1041844).

Author information

Authors and Affiliations

  1. Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University Wellington Road, Clayton, 3800, Victoria, Australia

    Katrina M. Mirabito Colafella & Kate M. Denton

  2. Department of Physiology, Monash University, 26 Innovation Walk, Clayton, 3800, Victoria, Australia

    Katrina M. Mirabito Colafella & Kate M. Denton

  3. Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands

    Katrina M. Mirabito Colafella

Authors
  1. Katrina M. Mirabito Colafella
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kate M. Denton
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.M.M.C. and K.M.D. researched the data, discussed the article's content, wrote the text and reviewed or edited the article before submission.

Corresponding authors

Correspondence to Katrina M. Mirabito Colafella or Kate M. Denton.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Hypertensive disorders of pregnancy

Hypertension that develops during pregnancy and is resolved following delivery of the offspring.

Polycystic ovary syndrome

(PCOS). A hormonal condition in which testosterone levels are elevated that is associated with irregular menstrual cycles, excessive facial and body hair, obesity, reduced fertility and increased risk of diabetes.

Hypothalamic hypoestrogenaemia

A condition in which plasma oestrogen levels are low owing to abnormal pituitary regulation of oestrogen.

Senescence-associated secretory phenotype

(SASP). A phenotype of senescent cells in which there is a high production of cytokines (IL-β1, tumour necrosis factor), chemokines (monocyte chemoattractant proteins), reactive oxygen species (superoxide) and remodelling factors (transforming growth factor–β), which results in recruitment of immune cells to the site of injury.

Cellular senescence

A process that results in permanent cellular proliferative arrest.

Sirtuins

NAD+-dependent deacetylases that act on forkhead homeobox transcription factors, peroxisome proliferator-activated receptor-α and nuclear factor-κB.

Telomere uncapping

Telomere ends form a loop structure, known as a cap, which prevents the chromosome ends from being recognized as double-stranded DNA breaks and initiating a DNA damage response. Telomere uncapping increases with advancing age and is associated with hypertension.

Oestrogenic compound

A compound with oestrogen-like activity. In women, there are three major endogenous oestrogenic compounds: estrone, oestradiol and estriol. In rodents, 17β-oestradiol is the major oestrogenic compound.

Radiotelemetry

The use of radio-waves to transmit information from a device to a remote receiver. This is the gold-standard method used to measure blood pressure (BP) in rodents, as BP can be measured continuously in unrestrained animals.

Tail-cuff plethysmography

A non-invasive method that uses plethysmography (volume displacement) to measure blood pressure (BP) in rodents via a cuff placed around the tail. This method is associated with stress and results in underestimation or overestimation of BP, but it is an inexpensive method that lends itself to long-term tracking of BP.

Sympathetic nervous system

(SNS). The part of the autonomic nervous system that serves to increase heart rate, constrict blood vessels and raise blood pressure when activated. Overactivity of the sympathetic nerves, particularly in the kidney, drives the development of hypertension.

Hyperandrogenaemia

A state characterized by androgen excess in females, for example, as seen in polycystic ovary syndrome.

Sex chromosome complement

The number and type of sex chromosomes present in an organism, with XY being usual in males and XX in females.

Four core genotype model

In the four core genotype (FCG) model, Sry, the testis-determining gene, is deleted from the Y chromosome and inserted into chromosome 3. In XY-male males (gonadal and chromosomal male), the autosome becomes male-determining instead of the Y chromosome. The FCGs are generated by crossing this XY-male (Sry on chromosome 3) with a wild-type XX-female, which gives XX-males (gonadal males with XX chromosomal complement), XY-males (gonadal males with XY chromosomal complement), XX-females (gonadal females with XX chromosomal complement) and XY-females (gonadal females with XY chromosomal complement).

Adoptive T cell transfer

The transfer of T cells into an individual; the cells may originate from the same subject or from another individual.

'Fat-but-fit' hypothesis

The hypothesis that cardiovascular fitness (and muscle mass) ameliorates the adverse impact of obesity on cardiometabolic health.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Colafella, K., Denton, K. Sex-specific differences in hypertension and associated cardiovascular disease. Nat Rev Nephrol 14, 185–201 (2018). https://doi.org/10.1038/nrneph.2017.189

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2017.189

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing