AMPK-YAP/TAZ signaling pathway mediates the amelioration of endothelial dysfunction elicited by moderate-intensity exercise-induced wall shear stress.

BACKGROUND: Arterial endothelial dysfunction is a critical early pathological change in cardiovascular diseases. Exercise-induced wall shear stress (WSS) exerts protective effects on impaired arterial endothelial function, while the underlying mechanism remains unclear. YAP/TAZ are core mechanotransduction molecules. This study aims to investigate whether YAP/TAZ mediate the ameliorative effect of moderate intensity exercise (MIE)-induced WSS on endothelial dysfunction via AMPK regulation. METHODS: Lipopolysaccharide (LPS)-injured HUVECs were exposed to MIE-induced WSS using a multicomponent parallel-plate flow chamber system. siRNA-mediated knockdown of AMPK and YAP was performed to verify the regulatory signaling pathway. In vivo, high-fat diet ApoE-/- mice received MIE intervention to assess the impacts of MIE on endothelial function and YAP expression. RESULTS: LPS induced YAP/TAZ activation and endothelial dysfunction, whereas MIE-induced WSS inhibited YAP/TAZ activation and reversed endothelial dysfunction in LPS-treated cells. YAP knockdown strengthened the ameliorative effect of MIE-induced WSS on endothelial dysfunction. Furthermore, AMPK knockdown promoted YAP activation and attenuated the beneficial impact of MIE-induced WSS on endothelial dysfunction. Consistently, MIE intervention reversed high-fat diet-induced impairment of common carotid arterial endothelial function, concurrent with YAP downregulation in vivo. These results indicate that MIE-induced WSS ameliorates endothelial dysfunction via activating AMPK, which in turn inhibits YAP/TAZ. CONCLUSIONS: This study provides novel insights into the molecular mechanism by which MIE-induced WSS alleviates endothelial dysfunction, and provides a theoretical foundation for the clinical application of MIE as a rehabilitation strategy to improve impaired arterial endothelial function.