The authors state that a 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. The authors hypothesized that alpha isoform of estrogen receptor (ERa) could be involved in the transduction of the vascular benefits of polyphenols.
The authors used ERa deficient mice to show that endothelium-dependent vasorelaxation induced either by red wine polyphenol extract, ProvinolsTM, or delphinidin, an anthocyanin that possesses similar pharmacological profile, is mediated by ERa. Indeed, ProvinolsTM, delphinidin and ERa agonists, 17-beta-estradiol and PPT, are able to induce endothelial vasodilatation in aorta from ERa Wild-Type but not from Knock-Out mice, by activation of nitric oxide (NO) pathway in endothelial cells. Besides, silencing the effects of ERa completely prevented the effects of ProvinolsTM and delphinidin to activate NO pathway (Src, ERK 1/2, eNOS, caveolin-1) leading to NO production. Furthermore, direct interaction between delphinidin and ERa activator site is demonstrated using both binding assay and docking. The investigators state that, most interestingly, the ability of short term oral administration of ProvinolsTM 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 ERa deficient mice. The authors conclude that this study provides evidence that red wine polyphenols, especially delphinidin, exert their endothelial benefits via ERa activation. They state that it is a major breakthrough bringing new insights of the potential therapeutic of polyphenols against cardiovascular pathologies.
Professor R Curtis Ellison comments: We are continually learning more of the mechanisms by which polyphenols present in wine and certain other beverages act to improve vascular function. This report is valuable in that it demonstrates quite clearly that estrogen receptor alpha plays an important, perhaps the most important, role in the metabolic pathway by which these polyphenols help reduce the risk of vascular disease. Mice bred to be without these estrogen receptors could not utilize polyphenols to increase nitric oxide production that leads to relaxation of blood vessels. Also, when this estrogen receptor was blocked in normal mice, there was no improvement in vascular function from these polyphenols. The findings from this paper provide important new mechanisms by which wine and other sources of polyphenols may prevent cardiovascular disease.
Source: Chalopin M, Tesse A, Mart?nez MC, Rognan D, Arnal J-F, Andriantsitohaina R. Estrogen receptor alpha as a key target of red wine polyphenols action on the endothelium. PLoS ONE 2010;5:e8554. doi:10.1371/journal.pone.0008554.