Orchidectomy, but not ovariectomy, regulates angiotensin II-induced vascular diseases in apolipoprotein E-deficient mice

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.