Proatherogenic effects of estradiol in a model of accelerated atherosclerosis in ovariectomized ApoE-deficient mice

Clinical studies revealed unfavorable effects of hormone replacement therapy in postmenopausal women despite strong evidence for vasoprotective effects of estrogen in animal models. Therefore, an attempt was made to address adverse effects of estradiol on atherosclerosis, endothelial function, and thrombosis in a murine model of atherosclerosis. ApoE(-/-) mice were bilaterally ovariectomized (OVX) and substituted with placebo or 17-beta-Estradiol (E(2), 1.1 and 6.6 mu g/day) on Western diet for 90 days. Low-dose E(2) (1.1 mu g/day) treatment significantly increased atherosclerotic plaque score, whereas high-dose E(2) (6.6 mu g/day) reduced aortic plaque burden. The proatherosclerotic effects of low-dose E(2) were associated with decreased total collagen in aortic root lesions and impaired acetylcholine (ACh)-induced vasorelaxation of aortic rings. On the contrary, OVX compared with control reduced atherosclerosis, increased fibrillar collagen and improved endothelial function. The thrombotic response as measured in a photothrombosis model was not significantly altered by E(2) or OVX. Taken together, differential effects on atherosclerosis of the clinical relevant low-dose E(2) compared with high-dose E(2) were demonstrated. Importantly, the presented experimental conditions provide a model to study the untoward vascular effects of E(2) in the context of accelerated and advanced atherosclerosis.