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

Graduate Center for Toxicology (T.A.H., J.H., A.D., L.A.C.), Division of Pharmaceutical Sciences (S.S.D., L.A.C.), Graduate Center for Nutritional Sciences (A.D., L.A.C.), and Departments of Medicine (A.D.) and Physiology (A.D.), University of Kentucky, Lexington, Kentucky 40536-0082

Address all correspondence and requests for reprints to: Lisa A. Cassis, Ph.D., Graduate Center for Nutritional Sciences, Room 521B, Wethington Building, University of Kentucky, Lexington, Kentucky 40536-0082. E-mail: lcassis{at}uky.edu.

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·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·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 mm², 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.

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