Susceptibility to Early Atherosclerosis in Male Mice Is Mediated by Estrogen Receptor α

Abstract

Objective— Vascular tissues express 2 types of estrogen receptors (ERs): ERα and ERβ. Their role in early atherosclerosis remains poorly understood, particularly in males. We developed and characterized an atherosclerosis model in ERα knockout male mice to investigate directly its role in atheroma. Methods and Results— Cholesterol-fed ERα knockout and wild-type mice developed early atheroma characterized by fatty streaks and foam cells. ERα 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 ERα knockout mice. Lesion development and atheroma susceptibility in ERα wild-type and knockout mice were independent of serum cholesterol, triglycerides, high-density lipoproteins, 17β-estradiol, and testosterone levels. In contrast, castration eliminated the predilection of ERα wild-type mice for atheroma, suggesting that testosterone mediates ERα-dependent atheroma formation in males. Conclusions— This study is the first to report that the ERα 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 ERα males. Our findings may have implications for selective targeting of ERα in atherosclerotic disease.