17-BETA-ESTRADIOL PREVENTS FATTY STREAK FORMATION IN APOLIPOPROTEIN E-DEFICIENT MICE

The reality of the atheroprotective effect of estrogens is still a mat ter of debate, and its unknown mechanisms could involve favorable chan ges 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 a ttempt 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 uncast rated (intact) animals. Total serum cholesterol, LDL-cholesterol, and HDL-cholesterol concentrations decreased under E-2 treatment in each s ex and were weakly correlated with lesion area. However, a highly sign ificant correlation between lesion area and serum E-2 levels also sugg ested a direct action of E-2 on cells of the vascular wall. A dose-res ponse curve analysis revealed that these activities were sex-dependent , with females being nearly twice as sensitive to E-2 as males. It als o 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 cleara nce rates.