The direct antiatherogenic effect of estrogen is present, absent, or reversed, depending on the state of the arterial endothelium - A time course study in cholesterol-clamped rabbits

Background-This study further investigated the relationship between estroge n, arterial endothelium, and nitric oxide (NO) in cholesterol-clamped rabbi ts. Methods and Results-Rabbits were ovariectomized, balloon-injured in the tho racic aorta, and grouped to receive cholesterol-enriched chow together with either 17 beta-estradiol or vehicle for 1, 2, 4, or 8 weeks. In the undama ged aorta, cholesterol accumulation of the placebo rabbits was significantl y increased from week 4 to 8 (P<0.001). This increase was almost completely inhibited by estrogen (P<0.001). In the balloon-injured aorta, the estroge n and placebo rabbits accumulated similar amounts of cholesterol in the ree ndothelialized areas. In the deendothelialized areas, the estrogen group su rprisingly accumulated significantly more cholesterol than the placebo grou p. This difference was apparent from week 2 and became significant at week 8 (P<0.01). Circulating nitrite/nitrate were significantly increased by est rogen at weeks 1, 2, and 4 but not at week 8, Similarly, in additional expe riments, basal NO release was significantly higher in estrogen-treated than in placebo-treated rabbits after 4 (P<0.05) but not after 8 weeks. Stimula ted NO release and endothelial NO synthase activity did not differ between groups. Mononuclear-endothelial cell binding was reduced by 50% by estrogen after 4 weeks (P<0.05), This difference, however, was abolished by coadmin istration of NG-nitro-L-arginine methyl ester, an inhibitor of NO productio n. Conclusions-The direct antiatherogenic effect of estrogen was present, abse nt, or reversed, depending on the state of the arterial endothelium, and pr eceded by a transient increase in NO production followed by a reduced monon uclear-endothelial cell binding.