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

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 17 beta-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.