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J. Biol. Chem., Vol. 280, Issue 9, 7460-7468, March 4, 2005

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Resveratrol and Estradiol Rapidly Activate MAPK Signaling through Estrogen Receptors and in Endothelial Cells^*

Carolyn M. Klinge, Kristy A. Blankenship, Kelly E. Risinger, Shephali Bhatnagar, Edouard L. Noisin, Wasana K. Sumanasekera, Lei Zhao, Darren M. Brey¶, and Robert S. Keynton¶

From the Department of Biochemistry & Molecular Biology and Center for Genetics and Molecular Medicine, School of Medicine and the ^¶Department of Mechanical Engineering, Speed School of Engineering, University of Louisville, Louisville, Kentucky 40292

Vascular endothelial cells (EC) are an important target of estrogen action through both the classical genomic (i.e. nuclear-initiated) activities of estrogen receptors and (ER and ER) 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 ER and ER. We demonstrate that resveratrol and estradiol (E₂) 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 E₂-induced MAPK and eNOS activation, indicating ER dependence. We demonstrate for the first time that ER-and ER-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.

Received for publication, October 12, 2004 , and in revised form, December 14, 2004.

^* This work was supported by American Heart Association Grant 0150818B (to C. M. K.), National Institutes of Health Grant RO1 DK 53220 (to C. M. K.), National Aeronautics and Space Administration Grant NAG5-12874 (to C. M. K. and R. S. K.), and American Heart Association Postdoctoral Fellowship 0425431B (to W. K. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 502-852-3668; Fax: 502-852-6222; E-mail: carolyn.klinge{at}louisville.edu.

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