Abstract 17/3-Estradiol has recently been found to inhibit atherogenesis by mechanisms that are in part independent of the estrogenic action on plasma lipoprotein levels. Since aortic permeability to low-density lipoprotein (LDL) in normocholesterolemic rabbits is a strong predictor for subsequent atherosclerosis during hypercholesterolemia, the present study investigated a possible influence of 17/3-estradiol on aortic permeability to LDL. Twenty rabbits were initially ovariectomized and then fed a nonatherogenic diet for 10 weeks. One group of rabbits (n=10) received 4 mg of 17/3-estradiol orally per day; the other group (n=10) received placebo. Serum concentrations of very-low-density lipoprotein cholesterol and triglycerides increased significantly more in the placebo group than in the estrogen group (p<.03), whereas there were no statistically significant differences between groups in LDL, high-density lipoprotein, or total cholesterol. At the end of the experiment, 125 I-LDL was injected intravenously into each rabbit. Aortas were removed 3 hours later, and the aortic permeability to LDL was calculated from the radioactivity in the plasma and the aortic intima/inner media. The aortic permeability to LDL was virtually identical in the 17/3-estradiol (31.6±7.2 nL cm" 2 h" 1) and the placebo (36.9±7.9 nL cm" 2 h~ !) groups (mean±SEM). The aortic cholesterol content was also similar in the two groups. These data suggest that the plasma lipid-independent antiatherogenic effect of estradiol is not mediated through an effect on aortic permeability to LDL but rather is related to the metabolism of the lipoproteins after they have entered the arterial wall.