Estrogen Receptor Alpha as a Key Target of Red Wine Polyphenols Action on the Endothelium

Matthieu Chalopin,Didier Rognan,Angela Tesse,Ramaroson Andriantsitohaina,Maria Carmen Martínez,Jean-François Arnal,Carlo Polidori

doi:10.1371/journal.pone.0008554

Abstract

BackgroundA greater reduction in cardiovascular risk and vascular protection associated with diet rich in polyphenols are generally accepted; however, the molecular targets for polyphenols effects remain unknown. Meanwhile evidences in the literature have enlightened, not only structural similarities between estrogens and polyphenols known as phytoestrogens, but also in their vascular effects. We hypothesized that alpha isoform of estrogen receptor (ERα) could be involved in the transduction of the vascular benefits of polyphenols.Methodology/Principal FindingsHere, we used ERα deficient mice to show that endothelium-dependent vasorelaxation induced either by red wine polyphenol extract, Provinols™, or delphinidin, an anthocyanin that possesses similar pharmacological profile, is mediated by ERα. Indeed, Provinols™, delphinidin and ERα agonists, 17-beta-estradiol and PPT, are able to induce endothelial vasodilatation in aorta from ERα Wild-Type but not from Knock-Out mice, by activation of nitric oxide (NO) pathway in endothelial cells. Besides, silencing the effects of ERα completely prevented the effects of Provinols™ and delphinidin to activate NO pathway (Src, ERK 1/2, eNOS, caveolin-1) leading to NO production. Furthermore, direct interaction between delphinidin and ERα activator site is demonstrated using both binding assay and docking. Most interestingly, the ability of short term oral administration of Provinols™ to decrease response to serotonin and to enhance sensitivity of the endothelium-dependent relaxation to acetylcholine, associated with concomitant increased NO production and decreased superoxide anions, was completely blunted in ERα deficient mice.Conclusions/SignificanceThis study provides evidence that red wine polyphenols, especially delphinidin, exert their endothelial benefits via ERα activation. It is a major breakthrough bringing new insights of the potential therapeutic of polyphenols against cardiovascular pathologies.

Highlights

Epidemiological studies have enlightened that women have lower cardiovascular risk than men, and this protection progressively disappears after menopause
Even if it has already been shown that both ProvinolsTM and delphinidin are able to induce nitric oxide (NO) production in endothelial cells [18], and that estrogens are able to increase NO production via estrogen receptor alpha (ERa) [21], here we demonstrate for the first time the direct link between the ability of ProvinolsTM and delphinidin to stimulate NO pathways leading to endothelial NO production through ERa activation
The present study identifies ERa as the, or at least one of, key receptor transducing vascular effects exerted by red wine polyphenols, delphinidin with respect to NO production

Summary

Introduction

Epidemiological studies have enlightened that women have lower cardiovascular risk than men, and this protection progressively disappears after menopause. Epidemiological studies reported a greater reduction in cardiovascular risk and greater vascular protection associated with diet rich in polyphenols, including those from red wine [5]. Intracellular pathways involved in the endothelial effects of polyphenols are partially described (increase of intracellular calcium, activation of tyrosine kinases, for instance) [7], the molecular targets of these polyphenols remain unknown. A greater reduction in cardiovascular risk and vascular protection associated with diet rich in polyphenols are generally accepted; the molecular targets for polyphenols effects remain unknown. We hypothesized that alpha isoform of estrogen receptor (ERa) could be involved in the transduction of the vascular benefits of polyphenols

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