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.

Sex-specific differences in hypertension and associated cardiovascular disease

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

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

  2. 2

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  4. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10

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

    PubMed  Article  PubMed Central  Google Scholar 

  11. 11

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12

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

    PubMed  PubMed Central  Article  Google Scholar 

  13. 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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  14. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  15. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  16. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  17. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  20. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 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. 28

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

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29

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

    PubMed  Article  PubMed Central  Google Scholar 

  30. 30

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

    CAS  Article  Google Scholar 

  31. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33

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

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  34. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  35. 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. 36

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

    PubMed  Article  PubMed Central  Google Scholar 

  37. 37

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

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 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. 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).

    CAS  Article  Google Scholar 

  41. 41

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

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

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

    PubMed  PubMed Central  Article  Google Scholar 

  44. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 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  PubMed Central  Google Scholar 

  47. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 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).

    PubMed Central  Article  CAS  Google Scholar 

  53. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 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  PubMed Central  Google Scholar 

  55. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 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. 63

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. 71

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 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  PubMed Central  Google Scholar 

  77. 77

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 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  PubMed Central  Google Scholar 

  79. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. 81

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. 82

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 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. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. 91

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  93. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. 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  PubMed Central  Google Scholar 

  95. 95

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  98. 98

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. 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  PubMed Central  Google Scholar 

  100. 100

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  102. 102

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  104. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. 105

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  106. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. 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  PubMed Central  Google Scholar 

  108. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  112. 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  PubMed Central  Google Scholar 

  113. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114

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

    Article  Google Scholar 

  115. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. 117

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. 118

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. 121

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

    PubMed  Article  PubMed Central  Google Scholar 

  122. 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  PubMed Central  Google Scholar 

  123. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  124. 124

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  127. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  130. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  133. 133

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  134. 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. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  136. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  137. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  138. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  140. 140

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141

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

    CAS  Article  Google Scholar 

  142. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  143. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  144. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  145. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  146. 146

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

    PubMed  PubMed Central  Article  Google Scholar 

  147. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  148. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  150. 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. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  152. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  153. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  154. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  155. 155

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  157. 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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  158. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  159. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  160. 160

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  162. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  163. 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  PubMed Central  Google Scholar 

  164. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. 165

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  166. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  167. 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).

    CAS  Article  Google Scholar 

  168. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  169. 169

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  170. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  171. 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  PubMed Central  Google Scholar 

  172. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  173. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. 174

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

    CAS  Article  Google Scholar 

  175. 175

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

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  176. 176

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  177. 177

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  178. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  179. 179

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  181. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. 183

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  185. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  186. 186

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  187. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  188. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  189. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  190. 190

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  192. 192

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  193. 193

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  194. 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).

    CAS  Article  Google Scholar 

  195. 195

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  197. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  198. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  199. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  200. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  201. 201

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. 202

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  203. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  204. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  205. 205

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  206. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  207. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  208. 208

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

    PubMed  Article  PubMed Central  Google Scholar 

  209. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  210. 210

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  211. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  212. 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. 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  PubMed Central  Google Scholar 

  214. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. 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  PubMed Central  Google Scholar 

  216. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  217. 217

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

    PubMed  Article  PubMed Central  Google Scholar 

  218. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  219. 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. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  221. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  222. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  223. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  224. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  225. 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).

    CAS  Article  Google Scholar 

  226. 226

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  227. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  228. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  229. 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. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  231. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  232. 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).

    CAS  Article  Google Scholar 

  233. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  234. 234

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  235. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  236. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  237. 237

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

    PubMed  PubMed Central  Article  Google Scholar 

  238. 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).

    PubMed Central  Article  CAS  Google Scholar 

  239. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  240. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  241. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  242. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  243. 243

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

  244. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  245. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  246. 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. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  248. 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).

    PubMed  Article  PubMed Central  Google Scholar 

  249. 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. 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. 251

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

    CAS  Article  Google Scholar 

  252. 252

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  253. 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. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  255. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  256. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  257. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  258. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  259. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  260. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  261. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  262. 262

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  263. 263

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  264. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  265. 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  PubMed Central  Google Scholar 

  266. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  267. 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).

    CAS  Article  Google Scholar 

  268. 268

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  269. 269

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

    CAS  PubMed  Article  PubMed Central  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

Affiliations

Authors

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

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

Further reading

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