Postmenopausal hormone replacement therapy and the vascular wall:: Mechanisms of 17 β-estradiol's effects on vascular biology

17 beta-estradiol (E-2) protects against atherosclerosis independent of changes in plasma lipoproteins in a variety of animal models, which is explained by direct effects of E-2 on the vascular wall. E-2 improves vasomotion by modulation of vasoconstrictor and vasodilator systems through endothelium-dependent and endothelium-independent mechanisms. E-2 affects the remodeling of the vascular wall by inhibiting smooth muscle cell proliferation and accelerating reendothelialization of injured blood vessels. E-2 modulates the vascular inflammatory response by inhibiting cytokine production, cytokine-induced expression of cell adhesion molecules and platelet aggregation/adhesion. This review focuses on the cellular and molecular mechanisms underlying these vasculoprotective actions of E-2. E-2 can act through nongenomic stimulation of membrane/intracellular mediators and/or the classical genomic pathway of steroid actions, which is dependent on transcription and protein synthesis. The existence of at least two nuclear estrogen receptor (ER) subtypes alpha and beta and a putative membrane ER present the potential of tissue-specific as well as biologically different E-2 actions. Nuclear ERs act as ligand-activated transcription factors and can affect gene regulation by interaction with the classical estrogen response element or other nonreceptor transcription factors. The molecular basis of genomic E-2 actions by identifying transcription factors and regulatory elements involved in the induction and inhibition of E-2 regulated gene expression is only at the beginning of being understood. The impact of E-2-mediated increased NO availability on the hemodynamic and antiatherosclerotic actions of E-2 is still a debate of controversy.