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  • Title: Estrogen receptor-mediated, nitric oxide-dependent modulation of the immunologic barrier function of the endothelium: regulation of fas ligand expression by estradiol.
    Author: Amant C, Holm P, Xu Sh SH, Tritman N, Kearney M, Losordo DW.
    Journal: Circulation; 2001 Nov 20; 104(21):2576-81. PubMed ID: 11714653.
    Abstract:
    BACKGROUND: Premenopausal women have a lower incidence of coronary artery disease than postmenopausal women or same-age men. Although the mechanisms of this apparent relative protection against atherosclerosis remain ill defined, estradiol, which is present in higher concentrations before menopause, is considered to play a central role. Recently, Fas ligand (FasL) expression by the vascular endothelium has been shown to inhibit the migration of inflammatory 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 estradiol was investigated in vivo and in vitro. In an ovariectomized, cholesterol-clamped rabbit model, FasL expression was shown to be downregulated by elevations in serum cholesterol, which also resulted in invasion of the arterial wall by macrophages. Estradiol replacement resulted in restoration of FasL expression, with resultant inhibition of leukocyte traffic across the endothelium. Inhibition of NO production by addition of L-NAME to the drinking water of the estradiol-treated rabbits abrogated these effects. In vitro, estradiol is shown to regulate FasL expression at the transcriptional level via an estrogen receptor-mediated, NO-dependent mechanism. CONCLUSIONS: Estradiol transcriptionally regulates endothelial FasL expression by a mechanism involving at least one of the estrogen receptors. In an animal model of atherosclerosis, estradiol restores FasL expression, which is suppressed by atherogenic levels of serum cholesterol. The maintenance of endothelial FasL expression by estradiol may represent a mechanism of estrogen's apparent antiatherogenic effect.
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