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Hypertension. 2005;46:475-476
Published online before print August 15, 2005, doi: 10.1161/01.HYP.0000178600.88820.b2
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(Hypertension. 2005;46:475.)
© 2005 American Heart Association, Inc.

Editorial Commentaries

Sex Differences in Cardiovascular Disease and Hypertension

Involvement of the Renin-Angiotensin System

Christine Maric

From the Department of Medicine and the Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University Medical Center, Washington, DC.

Correspondence to Christine Maric, PhD, Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University Medical Center, 394 Bldg D, 4000 Reservoir Rd NW, Washington, DC 20057. E-mail cm255{at}georgetown.edu

The incidence and the progression rate of cardiovascular disease and hypertension (CVDH) is markedly higher in men than in age-matched, premenopausal women.1 After menopause, this relationship no longer exists, and the incidence as well as the rate of progression of CVDH are very similar in women and men.1 Sex differences in CVDH have also been reported in animal models, including the spontaneously hypertensive rat and2 Dahl salt-sensitive rat,3 and ischemia-reperfusion injury.4 Although the mechanisms underlying these sex differences in the incidence and progression of CVDH are largely unknown, the role of sex hormones in modulating the activity of several regulatory systems, including the renin-angiotensin system (RAS), has been suggested. In addition, genetic differences, especially with respect to the RAS, have also been implicated in mediating sex differences in the incidence and progression of CVDH.

In the current issue of Hypertension, Okumura et al5 describe the relationship between the differential expression of angiotensin II type 2 (AT2) receptors in mediating vascular remodeling induced by polyethylene cuff placement around the femoral artery in the wild-type (Agtr2+) and AT2 receptor null (Agtr2–) mice. The major findings of this study are: (1) AT2 receptor expression is enhanced in the injured artery of the Agtr2+, and this is more pronounced in the females; (2) In the Agtr2+ mice, no significant differences in the expression of the AT1 receptor are observed in either males or females; (3) The degree of vascular injury, as evidenced by increases in neointimal formation, DNA synthesis, expression of monocyte chemoattractant protein-1, production of superoxide anion, and NADPH oxidase activity in the injured artery, is greater in males than females and is more pronounced in the Agtr2– than the Agtr2+ mice; (4) Administration of the AT1 receptor antagonist valsartan (1 mg/kg per day) decreases vascular injury more so in female than male Agtr2+ mice; (5) Sex differences in the protective effects of valsartan are less pronounced in the Agtr2– mice. This study provides evidence that sex differences in the degree of vascular injury, being more pronounced in males than females, may be partially explained by the enhanced expression of AT2 receptors in the female femoral arteries. This study also provides evidence that AT2 receptors mediate a protective effect of angiotensin II in vascular injury.

The fact that females are more protected from developing CVDH compared with males has gathered much interest in examining the contribution of sex hormones to the progression of these disease processes. Studies examining the effects of sex hormones in CVDH have provided novel insights into the mechanisms of their action but also raised controversies as to whether female sex hormones are protective and whether male sex hormones may, in some cases, exert adverse effects in their target organs. The role of estrogens in particular has been controversial. Although the initial reports from the Women’s Health Initiative (WHI) study showed some adverse effects of the combined conjugated equine estrogen plus progestin therapy on stroke and coronary artery disease,6 other clinical studies have shown that women with hysterectomy have a higher prevalence and incidence of CVDH,7 suggesting that the lack of ovarian hormones is associated with a greater rate of CVDH. Accumulating experimental data in the Dahl salt-sensitive rat8 and in the renal wrap hypertensive model9 also support the hypothesis that estrogens may indeed be beneficial in attenuating CVDH. The discrepancies between the findings of the WHI indicating adverse effects of estrogens and experimental data suggesting beneficial effects of estrogens stress the importance of further examining the contribution of estrogens in CVDH.

On the other end of the spectrum are the male sex hormones. The fact that the male gender is a risk factor for the incidence and progression of CVDH suggests that male sex hormones may contribute to the development and progression of these disease processes. For example, castration in the spontaneously hypertensive rat reduces hypertension.2 However, it is possible that it is the balance between estrogens and androgens that govern risk factors in CVDH. Collectively, there is compelling evidence that sex hormones, most likely via interaction with other regulatory systems including the RAS, play an important role in the pathophysiology of CVDH.

The study of Okumura et al5 adds important information to our pool of evidence that the severity of vascular injury is greater in males than females. The authors suggest that the underlying cause for this sex difference may be the lower expression of AT2 receptors in the injured arteries of male rats. This suggests that the AT2 receptors exert a protective effect in vascular injury, especially in females. The concept that AT2 receptors exert protective effects in CVDH has also been suggested by others.10 These studies suggest that the antiproliferative, antifibrotic, and blood pressure–lowering properties of AT2 receptors contribute to its beneficial effects in CVDH. The involvement of AT2 receptors in mediating sex differences in CVDH have also been suggested. Polymorphisms in the AT2 receptor have been linked to premature coronary artery disease in males.11 Differential expression and activity of other components of the RAS have also been implicated in mediating sex differences in CVDH. Ovariectomy increases the expression of AT1 receptors in mesenteric vessels of spontaneously hypertensive rats12 and in the adrenal gland of Sprague-Dawley rats,13 whereas it decreases AT2 receptors in the kidney of Wistar-Hanover rats.14 These studies also show that estradiol supplementation decreases AT1 and increases AT2 receptor expression. Much less is known about the effects of testosterone in regulating AT1 and AT2 receptors. In the rat epididymis, castration decreases the expression of AT1 receptors,15 whereas in renal proximal tubules extracted from dihydrotestosterone-treated rats, no differences in AT1 receptors are observed.16 These studies clearly demonstrate an interaction between sex hormones and the RAS; however, further studies are needed to determine the precise physiological significance of these interactions, especially in humans.

Jugdutt et al suggested that the attenuation of myocardial injury associated with AT1 receptor blockade is associated with upregulation of AT2 receptors.17 The study by Okumura et al5 similarly suggests that the beneficial effects of AT1 receptor blockade are not just mediated through abolishing the effects of AT1 receptors but, in fact, by angiotensin II–induced upregulation of AT2 receptors, especially in females. These findings may suggest that the benefits of AT1 receptor blockers (angiotensin receptor blocker [ARB]) and angiotensin-converting enzyme (ACE) inhibitors may be gender specific. The reports on sex differences in the efficacy of ACE inhibitors have been conflicting. Although some studies report similar effects in women and men,18 one study reported a marginally more beneficial effects of ACE inhibitors in men.19 Interestingly, side effects associated with ACE inhibition such as coughing occur more frequently in women than men.20 The efficacy of ARB seems to be equal in men and women;21 however, gender-specific analysis of side effects have thus far not been performed. Furthermore, the efficacy of ARB in postmenopausal women, in whom the estrogen modulation of the RAS is lost, has not been performed. Given the evidence that estrogen regulates the RAS, it could be predicted that ARB would be particularly beneficial in postmenopausal women. Future studies need to be conducted to examine this hypothesis.

The significance of the study by Okumura et al5 is 2-fold. First, it demonstrates the importance of the RAS, in particular, AT2 receptors in mediating sex differences in vascular injury. Second, and, in my personal opinion more important, it stresses the importance of examining the mechanisms underlying sex differences in CVDH. Future studies in this direction will not only contribute to our understanding of why females have a lower incidence of CVDH compared with males but may also lead to the development of gender-specific therapeutics that may offer protection against disease processes that show clear sex difference in their etiology and progression.


*    Footnotes
 
The opinions expressed in this editorial commentary are not necessarily those of the editors or of the American Heart Association.


*    References
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 *References
 

  1. Reckelhoff JF. Gender differences in the regulation of blood pressure. Hypertension. 2001; 37: 1199–1208.[Abstract/Free Full Text]
  2. Reckelhoff JF, Zhang H, Srivastava K, Granger JP. Gender differences in hypertension in spontaneously hypertensive rats: role of androgens and androgen receptor. Hypertension. 1999; 34: 920–923.[Abstract/Free Full Text]
  3. Rowland NE, Fregly MJ. Role of gonadal hormones in hypertension in the Dahl salt-sensitive rat. Clin Exp Hypertens A. 1992; 14: 367–375.[Medline] [Order article via Infotrieve]
  4. Wang M, Baker L, Tsai BM, Meldrum KK, Meldrum DR. Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury. Am J Physiol Endocrinol Metab. 2005; 288: E321–E326.[Abstract/Free Full Text]
  5. Okumura M, Iwai M, Ide A, Mogi M, Ito M, Horiuchi M. Sex difference in vascular injury and vasoprotective effect of valsartan are related to differential AT2 receptor expression. Hypertension. 2005; 46: 577–583.[Abstract/Free Full Text]
  6. Kuller LH. Hormone replacement therapy and risk of cardiovascular disease: implications of the results of the Women’s Health Initiative. Arterioscler Thromb Vasc Biol. 2003; 23: 11–16.[Abstract/Free Full Text]
  7. Howard BV, Kuller L, Langer R, Manson JE, Allen C, Assaf A, Cochrane BB, Larson JC, Lasser N, Rainford M, Van Horn L, Stefanick ML, Trevisan M. Risk of cardiovascular disease by hysterectomy status, with and without oophorectomy: the Women’s Health Initiative Observational Study. Circulation. 2005; 111: 1462–1470.[Abstract/Free Full Text]
  8. Hinojosa-Laborde C, Craig T, Zheng W, Ji H, Haywood JR, Sandberg K. Ovariectomy augments hypertension in aging female Dahl salt-sensitive rats. Hypertension. 2004; 44: 405–409.[Abstract/Free Full Text]
  9. Ji H, Menini S, Mok K, Zheng W, Pesce C, Kim J, Mulroney S, Sandberg K. Gonadal steroid regulation of renal injury in renal wrap hypertension. Am J Physiol Renal Physiol. 2005; 288: F513–F520.[Abstract/Free Full Text]
  10. Gross ML, Adamczak M, Rabe T, Harbi NA, Krtil J, Koch A, Hamar P, Amann K, Ritz E. Beneficial effects of estrogens on indices of renal damage in uninephrectomized SHRsp rats. J Am Soc Nephrol. 2004; 15: 348–358.[Abstract/Free Full Text]
  11. Alfakih K, Lawrance RA, Maqbool A, Walters K, Ball SG, Balmforth AJ, Hall AS. The clinical significance of a common, functional, X-linked angiotensin II type 2-receptor gene polymorphism (-1332 G/A) in a cohort of 509 families with premature coronary artery disease. Eur Heart J. 2005; 26: 584–589.[Abstract/Free Full Text]
  12. Silva-Antonialli MM, Tostes RC, Fernandes L, Fior-Chadi DR, Akamine EH, Carvalho MH, Fortes ZB, Nigro D. A lower ratio of AT1/AT2 receptors of angiotensin II is found in female than in male spontaneously hypertensive rats. Cardiovasc Res. 2004; 62: 587–593.[Abstract/Free Full Text]
  13. Wu Z, Maric C, Roesch DM, Zheng W, Verbalis JG, Sandberg K. Estrogen regulates adrenal angiotensin AT1 receptors by modulating AT1 receptor translation. Endocrinology. 2003; 144: 3251–3261.[Abstract/Free Full Text]
  14. Baiardi G, Macova M, Armando I, Ando H, Tyurmin D, Saavedra JM. Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat. Regul Pept. 2005; 124: 7–17.[CrossRef][Medline] [Order article via Infotrieve]
  15. Leung PS, Wong TP, Chung YW, Chan HC. Androgen dependent expression of AT1 receptor and its regulation of anion secretion in rat epididymis. Cell Biol Int. 2002; 26: 117–122.[CrossRef][Medline] [Order article via Infotrieve]
  16. Quan A, Chakravarty S, Chen JK, Chen JC, Loleh S, Saini N, Harris RC, Capdevila J, Quigley R. Androgens augment proximal tubule transport. Am J Physiol Renal Physiol. 2004; 287: F452–F459.[Abstract/Free Full Text]
  17. Jugdutt BI, Menon V. AT1 receptor blockade limits myocardial injury and upregulates AT2 receptors during reperfused myocardial infarction. Mol Cell Biochem. 2004; 260: 111–118.[CrossRef][Medline] [Order article via Infotrieve]
  18. Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Am Med Assoc. 2002; 288: 2981–2997.[Abstract/Free Full Text]
  19. Nelson MR, Reid CM, Krum H, Ryan P, Wing LM, McNeil JJ. Short-term predictors of maintenance of normotension after withdrawal of antihypertensive drugs in the second Australian National Blood Pressure Study (ANBP2). Am J Hypertens. 2003; 16: 39–45.[Medline] [Order article via Infotrieve]
  20. Os I, Bratland B, Dahlof B, Gisholt K, Syvertsen JO, Tretli S. Female preponderance for lisinopril-induced cough in hypertension. Am J Hypertens. 1994; 7: 1012–1015.[Medline] [Order article via Infotrieve]
  21. McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003; 362: 767–771.[CrossRef][Medline] [Order article via Infotrieve]

Related Article:

Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT2 Receptor Expression
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Hypertension 2005 46: 577-583. [Abstract] [Full Text] [PDF]



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