title: Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells.
abstract: Vascular endothelial cells (EC) are an important target of estrogen action through both the classical genomic (i.e. nuclear-initiated) activities of estrogen receptors alpha and beta (ERalpha and ERbeta) and the rapid "non-genomic" (i.e. membrane-initiated) activation of ER that stimulates intracellular phosphorylation pathways. We tested the hypothesis that the red wine polyphenol trans-resveratrol activates MAPK signaling via rapid ER activation in bovine aortic EC, human umbilical vein EC, and human microvascular EC. We report that bovine aortic EC, human umbilical vein EC, and human microvascular EC express ERalpha and ERbeta. We demonstrate that resveratrol and estradiol (E(2)) rapidly activated MAPK in a MEK-1, Src, matrix metalloproteinase, and epidermal growth factor receptor-dependent manner. Importantly, resveratrol activated MAPK and endothelial nitric-oxide synthase (eNOS) at nm concentrations (i.e. an order of magnitude less than that required for ER genomic activity) and concentrations possibly achieved transiently in serum following oral red wine consumption. Co-treatment with ER antagonists ICI 182,780 or 4-hydroxytamoxifen blocked resveratrol- or E(2)-induced MAPK and eNOS activation, indicating ER dependence. We demonstrate for the first time that ERalpha-and ERbeta-selective agonists propylpyrazole triol and diarylpropionitrile, respectively, stimulate MAPK and eNOS activity. A red but not a white wine extract also activated MAPK, and activity was directly correlated with the resveratrol concentration. These data suggest that ER may play a role in the rapid effects of resveratrol in EC and that some of the atheroprotective effects of resveratrol may be mediated through rapid activation of ER signaling in EC.
authors.affiliation: Department of Biochemistry & Molecular Biology and Center for Genetics and Molecular Medicine, School of Medicine, University of Louisville, Kentucky 40292, USA. carolyn.klinge@louisville.edu
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Klinge
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Blankenship
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Risinger
authors.forename: Shephali
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Edouard L
authors.initials: EL
authors.lastname: Noisin
authors.forename: Wasana K
authors.initials: WK
authors.lastname: Sumanasekera
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Darren M
authors.initials: DM
authors.lastname: Brey
authors.forename: Robert S
authors.initials: RS
authors.lastname: Keynton
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism; D015153:Blotting, Western; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry; D000077267:Fulvestrant; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008833:Microcirculation / Q000166:cytology; D008954:Models, Biological; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010636:Phenols / Q000737:chemistry; D010766:Phosphorylation; D059808:Polyphenols; D000077185:Resveratrol; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013267:Stilbenes / Q000378:metabolism / Q000494:pharmacology*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology; D014920:Wine
chemical_list: D020533:Angiogenesis Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D013267:Stilbenes; D013629:Tamoxifen; C016601:afimoxifene; D000077267:Fulvestrant; D012694:Serine; D004958:Estradiol; D004815:Epidermal Growth Factor; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D048369:MAP Kinase Kinase 1; D000077185:Resveratrol