title: Postmenopausal hormone replacement therapy and the vascular wall: mechanisms of 17 beta-estradiol's effects on vascular biology.
abstract: 17 beta-estradiol (E2) protects against atherosclerosis independent of changes in plasma lipoproteins in a variety of animal models, which is explained by direct effects of E2 on the vascular wall. E2 improves vasomotion by modulation of vasoconstrictor and vasodilator systems through endothelium-dependent and endothelium-independent mechanisms. E2 affects the remodeling of the vascular wall by inhibiting smooth muscle cell proliferation and accelerating reendothelialization of injured blood vessels. E2 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 E2. E2 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 E2 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 E2 actions by identifying transcription factors and regulatory elements involved in the induction and inhibition of E2 regulated gene expression is only at the beginning of being understood. The impact of E2-mediated increased NO availability on the hemodynamic and antiatherosclerotic actions of E2 is still a debate of controversy.
authors.affiliation: Dept. of Internal Medicine I, Endocrinology and Metabolism, University of Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Joswig
authors.forename: V
authors.initials: V
authors.lastname: Hach-Wunderle
authors.forename: R
authors.initials: R
authors.lastname: Ziegler
authors.forename: P P
authors.initials: PP
authors.lastname: Nawroth
mesh_terms: D016207:Cytokines / Q000096:biosynthesis; D004958:Estradiol / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010974:Platelet Aggregation; D017698:Postmenopause / Q000187:drug effects*; D011960:Receptors, Estrogen / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D009569:Nitric Oxide; D004958:Estradiol; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III