Effect of 17β-estradiol in hypercholesterolemic rabbits with severe endothelial dysfunction.

17β-Estradiol prevents early vascular lesion development and may also affect advanced atherosclerosis. To test the antiatherosclerotic effect of estrogen under conditions that resemble more advanced human atherosclerosis with severe endothelial dysfunction, we have investigated the effect of 17β-estradiol in hypercholesterolemic rabbits treated with the nitric oxide synthase inhibitor N ω-nitro-l-arginine methyl ester (l-NAME). Chronicl-NAME administration attenuated endothelial nitric oxide (EDNO)-mediated vascular responses leading to significantly accelerated atherosclerotic plaque development. 17β-Estradiol treatment alone inhibited aortic lesion formation with concurrent increase in EDNO-mediated responses. The beneficial effect of estrogen persisted in thel-NAME-treated rabbits, suggesting that the antiatherogenic action of 17β-estradiol involves NO-independent mechanisms as well. Serum cholesterol levels were not altered by any of the treatments. 17β-Estradiol treatment significantly increased EDNO production under these conditions as well. The reduction in plaque size by 17β-estradiol was always accompanied by increased EDNO production, suggesting a strong association between these two events. The results demonstrate that estrogen treatment may exert protection against atherosclerosis even in patients with severe endothelial dysfunction.