We have studied the effects of endogenous and exogenous estrogen on atherosclerotic lesions in apolipoprotein E-deficient mice. Female mice ovariectomized (OVX) at weaning displayed increases (P < 0.01) in fatty streak lesions in the proximal aorta and aortic sinus compared with female mice with intact ovarian function. These differences between the OVX and sham controls were apparent in both chow-and "Western-type" diet-fed mice. Moreover, increases in lesion size following OVX occurred without changes in plasma cholesterol. Hormone replacement with subdermal 17-8-estradiol pellets releasing either 6, 14, or 28 jig/day significantly decreased (P < 0.001) atherosclerotic lesion area in both male and OVX female mice. In contrast, neither 17-a-estradiol (28 ,ig/day) or tamoxifen (85 ,ig/day) affected lesion progression in OVX female mice. In the Western diet-fed group, exogenous estradiol markedly reduced plasma cholesterol and triglycerides, whereas, in animals fed the chow diet, exogenous estrogen and tamoxifen treatment only decreased plasma and very low density lipoprotein triglycerides. However, lesion area was only weakly correlated with plasma cholesterol and triglycerides, 0.35 and 0.44 tau values, respectively (P < 0.01). In summary, in the apolipoprotein E-deficient mouse 17-j8-estradiol protects against atherosclerotic lesion formation, and this can only be partially explained through effects on plasma lipoprotein levels. Cardiovascular diseases resulting from atherosclerosis are a leading cause of death in Western societies (1). Epidemiological studies show men and postmenopausal women are at higher risk for such diseases than are premenopausal women, suggesting that estrogen may be cardioprotective (2, 3). This reduction in risk for cardiovascular disease is caused in part by the effects of estrogen on lipoprotein metabolism and shifts of the plasma lipoproteins to a less atherogenic profile (4). Estrogen, particularly when taken orally, lowers plasma low density lipoprotein (LDL) and raises high density lipoprotein (HDL) levels (5, 6). Although these lipoprotein changes occur in premenopausal women and postmenopausal women receiving hormone replacement therapy, in large-scale studies with adjustments for multiple risk factors, only 25-50% of the beneficial effects of estrogen appear to be due to lipoprotein effects (7).The nonlipid effects of estrogen that may contribute to the cardioprotection observed in humans include the following: effects on endothelial metabolism (8, 9), myocardial conductance, hemostatic factors (10, 11), vascular tone and reactivity (12), intimal cell proliferation (13, 14), Lp(a) levels (15), expression of adhesion molecules (16), platelet aggregation (17), LDL oxidation (18, 19), inflammatory cytokine expression (20, 21), and extracellular matrix synthesis. Additionally, estrogen might affect arterial wall calcification (22), the formation of unstable plaque and the generation of occlusive thrombi (4).Detailed systematic evaluation of these parameters in vivo requir...