17β-Estradiol Prevents Fatty Streak Formation in Apolipoprotein E–Deficient Mice

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Abstract
Abstract The reality of the atheroprotective effect of estrogens is still a matter of debate, and its unknown mechanisms could involve favorable changes in blood lipids and lipoproteins and/or direct action at the level of the arterial wall. We used the recently developed animal model of atherosclerosis constituted by apolipoprotein E–deficient mice in an attempt to clarify these issues. Male and female animals, fed a low-fat chow diet, were treated with increasing doses of 17β-estradiol (E 2 ) after castration and compared with testosterone treated and uncastrated (intact) animals. Total serum cholesterol, LDL-cholesterol, and HDL-cholesterol concentrations decreased under E 2 treatment in each sex and were weakly correlated with lesion area. However, a highly significant correlation between lesion area and serum E 2 levels also suggested a direct action of E 2 on cells of the vascular wall. A dose-response curve analysis revealed that these activities were sex-dependent, with females being nearly twice as sensitive to E 2 as males. It also revealed that the atheroprotective activity was recruited at higher E 2 concentrations than those needed by other E 2 target tissues such as uterus or functions such as apoA-1 and LDL production and/or clearance rates.