Targeting Endothelial Progenitor Cells Reparative Potential Via Canonical Wnt/NOX-4 Signaling Pathway in Rats Dyslipidemia: Role of Resveratrol

Abstract

Signaling pathways guiding the reparative function of endothelial progenitor cells (EPCs) are complex. Conflicts involve the double-face role of NADPH oxidase-4 (NOX-4) and canonical Wnt/ β-catenin pathways in endothelial dysfunction. Resveratrol confers vasoprotection, yet its molecular mechanism is not clearly delineated. The study investigated whether targeting Wnt/β-catenin/NOX-4 signaling pathway could improve EPC repair in dyslipidemia, and whether it is a therapeutic target for resveratrol vasoprotection. Thirty-six Wistar rats were assigned as normal or dyslipidemic and fed on standard-chow or high-fat diet (HFD), respectively. Dyslipidemic rats received an 8-week oral vehicle or resveratrol (10 mg/kg/day). Eight weeks later, body and visceral-fat weights, and lipid profiles were assessed. Aortae were dissected for histopathological examination and immunohistochemical assessment of the EPC marker (CD133/VEGF receptor-2), and b-catenin expression. Aortic NOX-4 mRNAexpression and vascular function were performed. EPC regenerative capacity evidenced by their count and vascular reactivity was reduced by dyslipidemia. Dysregulation of endothelial Wnt/ β-catenin signaling, and NOX-4 expression were noted in conjunction with endothelial atherogenesis and oxidative stress. Resveratrol conferred endothelial protection, anti-atherogenic, and antioxidant action in HFD-fed rats. Improvement of EPC reparative potential played a pivotal role in resveratrol vasoprotection and was mediated by an endothelial Wnt/ β-catenin/NOX-4 signaling crosstalk, constituting a novel therapeutic target for improving EPC repair profile in dyslipidemia.