Orchidectomy, But Not Ovariectomy, Regulates Angiotensin II-Induced Vascular Diseases in Apolipoprotein E-Deficient Mice

Abstract

In humans, the incidence and severity of abdominal aortic aneurysms (AAA) are greater in males than in females. Chronic infusion of angiotensin II (AngII) into apolipoprotein E-deficient (apoE(-/-)) mice promotes atherosclerosis and causes the formation of AAAs. Just as human males are more susceptible to developing AAAs, male mice are more susceptible to AngII-induced AAAs. We hypothesized that sex steroid hormones mediate gender differences in AngII-induced AAA through regulation of the renin-angiotensin system. To define the role of ovarian hormones, female apoE(-/-) mice were subjected to ovariectomy or sham operation and infused with AngII (1000 ng/kg x min) for 28 d. Ovariectomy had no effect on AngII-induced atherosclerosis, nor did it influence the incidence or severity of AAA. To define the role of testicular hormones, male apoE(-/-) mice were subjected to orchidectomy (orx) or sham operation and infused with AngII (1000 ng/kg x min) for 28 d. Orx resulted in a profound reduction in AAA incidence (85% vs. 18%, sham vs. orx; P = 0.003) to the level observed in females (25%). However, orx had no effect on AngII-induced reductions in plasma renin concentration or spleen AngII receptor density. In contrast, orx resulted in an increase in atherosclerosis (0.46 +/- 0.07 vs. 1.20 +/- 0.21 mm(2), sham vs. orx; P = 0.002). These results suggest that estrogen does not mediate gender differences in AngII-induced AAA. In contrast, androgens mediate a higher incidence of AngII- induced AAA, through mechanisms that do not appear to involve circulating renin or angiotensin receptor density.

Sex Differences in Abdominal Aortic Aneurysm: The Role of Sex Hormones

“…67 Androgens increased the incidence of AngII-induced AAA in mice and had the ability to stimulate MMP2 expression. 75 The effects of androgens on AAA formation include stimulation of components of the renineangiotensin system producing either increased synthesis or responsiveness to AngII. 75 Despite the many detrimental effects of testosterone, some studies revealed that androgens exert atheroprotective effects against cardiovascular disease at least in the elderly people, mediated by the androgen receptors.…”

“…The incidence of AAA was strikingly reduced in orchiectomized male mice compared with sham controls (18% vs. 85%) and was similar to the incidence observed in female mice (25%). 75 Castrated male mice and rats treated with dihydrotestosterone and testosterone, respectively, showed a significant increase in the incidence of AAA compared with only castrated males. 69,76 Recently, a study by the same group showed that castration reduced the progressive lumen dilatation of established AAAs, suggesting that androgens also play a role in the progression of AAAs in male mice and that TGFb and Serpine1 may be targets of testosterone action in the progression of AAA.…”

“…69 Wu et al 70 found SMCs disorganization, inflammatory cell infiltration, partial elastic fiber degradation, larger aneurysm size, and increased MMP2 and MMP9 mRNA levels in ovariectomized female rats, illustrating also the anti-inflammatory/antiproteolytic effects of estrogen in the elastase-induced AAA model. On the other hand, Henriques et al 75 showed that murine ovariectomy failed to significantly modify neither the incidence nor the severity of the AngII-induced AAAs, indicating that the endogenous ovarian hormones are not the primary mediators of sex differences in AngII-induced AAA. Finally, aromatase deletion further increased aortic dilatation compared with wild-type ovariectomized females, suggesting that the protective effect of female sex on AAA requires the presence of both ovarian and extragonadal/peripheral aromatase.…”

Bone Marrow Transplantation Reveals That Recipient AT1a Receptors Are Required to Initiate Angiotensin II–Induced Atherosclerosis and Aneurysms

“…5 Thus, AngII provides a common stimulus for atherosclerosis and AAAs, but the development of these pathologies appears to occur via distinct mechanisms. 6 The specific receptor regulating the formation of AngII-induced atherosclerosis has not been determined. A role for AT1 receptors in AngII-induced AAAs has been demonstrated by inhibition with losartan, although the contribution of AT1a versus AT1b receptors has not been defined.…”

A population-based study of polymorphisms in genes related to sex hormones and abdominal aortic aneurysm

“…1 Currently, the reasons for the male propensity for AAA are not known, but maybe linked to sex hormones, as in experimental models androgens have been positively linked to aortic dilatation. 2 The production, metabolism and response to sex hormones are controlled by an array of enzymes and receptors, including steroid 5a reductase, aromatase (estrogen synthetase), androgen and estrogen receptors. 3,4 Steroid 5a reductase enzymes are responsible for the conversion of testosterone to the more potent androgen dihydrotestosterone.…”