on April 29, 2004
Published online before print April 29, 2004, doi: 10.1161/01.ATV.0000130467.65290.d4
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Submitted on January 29, 2004
Accepted on April 19, 2004
Susceptibility to Early Atherosclerosis in Male Mice is Mediated by Estrogen Receptor 
Amparo Villablanca *;
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.
* To whom correspondence should be addressed. E-mail: avillablanca{at}ucdavis.edu.
Objective--Vascular tissues express 2 types of estrogen receptors (ERs): ER
and ER
. 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, and twice the number of lesions, all 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, 17-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.
Key words: vascular • hormone • lipids • gender • atheroma • aromatase • estrogen • testosterone
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