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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1055.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Amparo Villablanca; Dennis Lubahn; Lauren Shelby; Kent Lloyd; Stephen Barthold

From the Department of Internal Medicine (A.V., L.S.), University of California, Davis; the Department of Biochemistry (D.L.), University of Missouri, Columbia; and the Center for Comparative Medicine (K.L., S.B.), University of California, Davis.

Correspondence to Amparo C. Villablanca, MD, Associate Professor, Cardiovascular Medicine, University of California, Davis, Division of Cardiovascular Medicine, One Shields Ave, TB 172, Davis, CA 95616-8636. E-mail avillablanca{at}ucdavis.edu

Objective— Vascular tissues express 2 types of estrogen receptors (ERs): ER and ERß. Their role in early atherosclerosis remains poorly understood, particularly in males. We developed and characterized an atherosclerosis model in ER knockout male mice to investigate directly its role in atheroma.

Methods and Results— Cholesterol-fed ER knockout and wild-type mice developed early atheroma characterized by fatty streaks and foam cells. ER 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 ER knockout mice. Lesion development and atheroma susceptibility in ER wild-type and knockout mice were independent of serum cholesterol, triglycerides, high-density lipoproteins, 17ß-estradiol, and testosterone levels. In contrast, castration eliminated the predilection of ER wild-type mice for atheroma, suggesting that testosterone mediates ER-dependent atheroma formation in males.

Conclusions— This study is the first to report that the ER 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 ER males. Our findings may have implications for selective targeting of ER in atherosclerotic disease.

The role of ERs ER and ERß in early atherosclerosis remains poorly understood in males. We developed and characterized an atherosclerosis model in ER knockout male mice to investigate directly its role in atheroma. In males, the ER mediates susceptibility to early atherosclerosis by a testosterone-dependent pathway.

Key Words: vascular • hormone • lipids • gender • atheroma • aromatase • estrogen • testosterone

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