Estrogen increases apoptosis in the arterial wall in a murine atherosclerosis model

ObjectiveTo investigate the effect of estrogen (E) on vascular apoptosis during atherosclerotic plaque formation.DesignLaboratory study using a murine atherosclerosis model.SettingAcademic research center.Animal(s)Female mice homozygous for null alleles of LDL receptor (LDL-R−/−) in a C57BL/6 background. LDL-R−/− mice develop atherosclerosis in a predictable manner when fed a high cholesterol diet.Intervention(s)Eight-week-old female LDL-R−/− mice (n = 68) were ovariectomized, and implanted subcutaneously with 90-day release pellets containing 0.5 mg of 17β-estradiol (E2) or placebo. Four animals were evaluated at the initiation of the study. Thereafter, four animals from each group were sacrificed weekly for 8 weeks and their aortas studied.Main Outcome Measure(s)The effect of E2 on atherosclerotic plaque development, apoptosis, and cell proliferation was examined in the aorta of ovariectomized LDL-R−/− mice that were fed a high cholesterol diet.Result(s)Mice treated with E2 displayed a delay in atherosclerotic plaque formation, associated with an increase in DNA strand breaks in the arterial wall indicative of increased apoptosis, compared to placebo-treated mice. The two groups did not differ in mitotic activity.Conclusion(s)In female LDL-R−/− mice fed a high cholesterol diet, ovariectomy is associated with increased atherogenesis. The effect of ovariectomy on atherogenesis is reversed by E2 treatment. In addition to delayed atherogenesis, E2 treatment of ovariectomized LDL-R−/− mice results in an increase in apoptosis in the aortic wall without an effect on the mitotic activity. Our findings suggest that vascular effects of E may be in part mediated by a proapoptotic activity.