Susceptibility to early atherosclerosis in male mice is mediated by estrogen receptor alpha.

OBJECTIVE Vascular tissues express 2 types of estrogen receptors (ERs): ERalpha and ERbeta. Their role in early atherosclerosis remains poorly understood, particularly in males. We developed and characterized an atherosclerosis model in ERalpha knockout male mice to investigate directly its role in atheroma. METHODS AND RESULTS Cholesterol-fed ERalpha knockout and wild-type mice developed early atheroma characterized by fatty streaks and foam cells. ERalpha wild-type mice developed 3.8-fold greater lesion area, more advanced lesions, more extensive lesion distribution, twice the number of lesions, and at a 2.2-fold faster rate than ERalpha knockout mice. Lesion development and atheroma susceptibility in ERalpha wild-type and knockout mice were independent of serum cholesterol, triglycerides, high-density lipoproteins, 17beta-estradiol, and testosterone levels. In contrast, castration eliminated the predilection of ERalpha wild-type mice for atheroma, suggesting that testosterone mediates ERalpha-dependent atheroma formation in males. CONCLUSIONS This study is the first to report that the ERalpha mediates susceptibility to early atherosclerosis in male mice by a testosterone-dependent pathway, suggesting that local production of estrogen from testosterone in the vessel wall may promote atheroma formation in ERalpha males. Our findings may have implications for selective targeting of ERalpha in atherosclerotic disease.