Estrogen receptor-mediated, nitric oxide-dependent modulation of the immunologic barrier function of the endothelium - Regulation of Fas ligand expression by estradiol

Background-Premenopausal women have a lower incidence of coronary artery di sease than postmenopausal women or same-age men. Although the mechanisms of this apparent relative protection against atherosclerosis remain ill defin ed, estradiol, which is present in higher concentrations before menopause, is considered to play a central role. Recently, Fas ligand (FasL) expressio n by the vascular endothelium has been shown to inhibit the migration of in flammatory cells into the vessel wall, an event that is considered crucial for the development of atherosclerosis. Methods and Results-The regulation of endothelial FasL expression by estrad iol was investigated in vivo and in vitro. In an ovariectomized, cholestero l-clamped rabbit model, FasL expression was shown to be downregulated by el evations in serum cholesterol, which also resulted in invasion of the arter ial wall by macrophages. Estradiol replacement resulted in restoration of F asL expression, with resultant inhibition of leukocyte traffic across the e ndothelium. Inhibition of NO production by addition of L-NAME to the drinki ng water of the estradiol-treated rabbits abrogated these effects. In vitro , estradiol is shown to regulate FasL expression at the transcriptional lev el via an estrogen receptor-mediated, NO-dependent mechanism. Conclusions-Estradiol transcriptionally regulates endothelial FasL expressi on by a mechanism involving at least one of the estrogen receptors. In an a nimal model of atherosclerosis, estradiol restores FasL expression, which i s suppressed by atherogenic levels of serum cholesterol. The maintenance of endothelial FasL expression by estradiol may represent a mechanism of estr ogen's apparent antiatherogenic effect.