Rapid, estrogen receptor-mediated signaling: why is the endothelium so special?
Classical, ligand-activated genomic effects of estrogen receptors (ERs) were once thought to mediate all estrogen responses. It is now accepted that rapid, nongenomic responses, mediated by ER-containing membrane complexes, occur in many tissues. The endothelium is a major target of such responses and is the critical regulatory tissue that, when normally functional, determines a state of "vascular health." When dysfunctional, the phenotypic and functional alterations result in vascular pathology, the most common form of which is atherosclerosis. Nitric oxide (NO) is a vascular protective substance generated by endothelial NO synthase (eNOS) in endothelial cells. The engagement of membrane ERs by 17beta-estradiol (E2) is a potent stimulus to eNOS activation and NO release. Here, we describe the multimolecular components of ER-containing membrane complex assembly and the mechanisms directing ER targeting to caveolae microdomains in the plasma membrane. We discuss the possibility that various ERalpha splice forms, expressed in endothelial cells, may be particularly efficient signal transducers and may use classical receptor domains for membrane targeting and insertion. Finally, we discuss the biomedical ramifications of ER-mediated endothelial activation, including the controversies surrounding hormone replacement therapy and cardiovascular disease.
Kim
Kyung Hee
KH
Division of Cardiovascular Medicine, Raymond and Beverly Sackler Foundation Cardiovascular Laboratory, Yale University School of Medicine, New Haven, CT 06510, USA.
Bender
Jeffrey R
JR
D000328:Adult; D000368:Aged; D000818:Animals; D021941:Caveolae / Q000502:physiology; D003327:Coronary Disease / Q000453:epidemiology / Q000503:physiopathology / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology*; D004789:Enzyme Activation; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000502:physiology*; D017698:Postmenopause; D017697:Premenopause; D020033:Protein Isoforms / Q000502:physiology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology; D016032:Randomized Controlled Trials as Topic; D011960:Receptors, Estrogen / Q000502:physiology*; D017678:Sex Distribution; D015398:Signal Transduction / Q000502:physiology*
D020033:Protein Isoforms; D011960:Receptors, Estrogen; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D016392:Proto-Oncogene Proteins pp60(c-src)