Ex vivo to in vivo extrapolation of syringic acid and ferulic acid as grape juice proxies for endothelium-dependent vasodilation: Redefining vasoprotective resveratrol of the French paradox.

Resveratrol, in wines, has been implicated to be primarily responsible for the French paradox, remaining controversial. Herein, we elucidated the representative vasodilation-increasing polyphenols from concord grape juice (CGJ) using ex vivo-to-in vivo extrapolation (EVIVE). We verified the interference-free antioxidant response of CGJ post-dose supernatant of deproteinated serum (CPSDS, as ex vivo proxy) in isolated aortic rings, and in healthy, and HO-treated endothelial cells (H-ECs). Syringic acid and ferulic acid (SF) were detected in CGJ and post-dose rat serum (PRS). In isolated aortic rings and H-ECs, polyphenols alone, or in combination, at doses equivalent to those detected in PRS, quantitatively reflected endothelium-dependent vasodilation of CPSDS, as evidenced by nitric oxide (NO) formation-mediated antioxidation-sensitive activation of Src kinase with subsequent PI3/Akt-dependent phosphorylation of endothelial NO synthase. Using EVIVE, SF closely reflected CGJ in coronary flow-mediated vasodilation. Hence, SF application in precision ethnomedicine may redefine antioxidant-sensitive vasoprotective resveratrol of the French paradox.