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.

Objective-Castration of male apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice reduces angiotensin II (Ang II)-induced abdominal aorta aneurysms (AAAs) to that of female mice. The purpose of this study was to determine whether this reduction is attributable to androgen-mediated regulation of aortic Ang II type 1A receptors (AT1aR). Methods and Results-AT1aR mRNA abundance in the AAA-prone region of abdominal aortas was 8-fold greater compared to thoracic aortas of male but not female mice. AT1aR mRNA abundance decreased after castration in abdominal but not thoracic aortas of male mice. Dihydrotestosterone (DHT, 0.16 mg/d) administration to castrated male mice restored AT1aR mRNA abundance in abdominal aortas but had no effect in thoracic aortas. DHT also increased AT1aR mRNA abundance in abdominal aortas from female mice. Castrated male or female apoE Ϫ/Ϫ mice were administered DHT during infusion of saline or Ang II (1000 ng/kg/min for 28 days). DHT administration did not alter serum cholesterol concentrations, lipoprotein distributions, or atherosclerotic lesion areas in either male or female mice. However, administration of DHT increased AAA incidence in male (27% placebo versus 75% DHT) and female mice (28% placebo versus 64% DHT). Key Words: angiotensin Ⅲ aneurysms Ⅲ androgen Ⅲ atherosclerosis Ⅲ sex hormones A bdominal aortic aneurysms (AAAs) account for 2% of all deaths and are the tenth most common cause of mortality. 1 The incidence and severity of abdominal aortic dilations are greater in males than females. 2,3 Male gender has been consistently identified as a nonmodifiable risk factor for AAA. However, the role of androgens as mediators of gender differences in AAA has not been investigated extensively. Conclusions-AndrogenGender differences also impact AAA formation in experimental models of this disease. In aortic dilation promoted by transient intraluminal elastase infusion, male rats had larger and more frequent AAAs than females. 4 Chronic infusion of angiotensin II (Ang II) into hyperlipidemic mice resulted in AAA formation at a higher incidence in male compared to female mice. [5][6][7][8] In agreement with a potential protection of female gender, estradiol administration to male apolipoprotein E (apoE)-deficient mice reduced Ang II-induced AAA formation. 9 However, ovariectomy of apoE Ϫ/Ϫ mice did not significantly influence AAA formation, suggesting that endogenous ovarian hormones are not primary mediators of gender differences in Ang II-induced AAAs. 8 In contrast, removal of male sex hormones by orchiectomy of apoE Ϫ/Ϫ mice significantly reduced the incidence of Ang II-induced AAAs to that observed in female mice. 8 These data potentially implicate androgen as a primary mediator of gender differences in Ang II-induced AAAs; however, mechanisms of androgen to promote AAA formation are unknown.Androgen has been reported to increase the expression of each component of the renin-angiotensin system (RAS), including angiotensinogen, renin, ACE, and AT1 receptors. 10 Previous studies in our laboratory...

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