Author(s): LIU, X., Institution: XI’AN JIAOTONG UNIVERSITY, Country: CHINA, Abstract-ID: 559

INTRODUCTION:
Physical exercise improves hyperlipidemia-induced endothelial injury by reducing circulatory lipid levels and enhancing mitochondrial function in vascular endothelial cells. However, the exact mechanism underlying its protective effects remains uncertain, despite recent research indicating that blood flow shear stress is a key mechanism through which exercise enhances endothelial function. It is still unclear whether blood flow shear stress contributes to the exercise-induced improvement of endothelial injury caused by hyperlipidemia, and the specific mitochondrial molecular mechanism remains to be elucidated. Piezo1, as a newly discovered mechanosensitive ion channel protein, plays a crucial role in response to mechanical stress.
METHODS:
In this study, we utilized long-term and short-term hyperlipidemia models to elucidate the role of exercise in improving vascular damage caused by hyperlipidemia and whether fluid shear stress is involved. Furthermore, pharmacological interventions (PIEZO1 agonists and inhibitors) and PIEZO1 knockout mice were employed to validate PIEZO1 as a key molecule in exercise-induced improvement of hyperlipidemia-associated vascular damage. Finally, utilizing cellular and molecular biology techniques, we elucidated the molecular mechanism by which fluid shear stress promotes mitochondrial fusion through PIEZO1, thereby improving endothelial function.
RESULTS:
This study demonstrated that exercise can increase blood flow shear stress and ameliorate endothelial injury in both long-term and acute hyperlipidemia models. Additionally, intravenous injection of the Piezo1 agonist Yoda1 into the tail vein has a similar effect to exercise in mitigating endothelial injury. Conversely, the beneficial effects of exercise in improving endothelial injury diminish in endothelial-specific Piezo1 knockout mice and following intravenous injection of the Piezo1 inhibitor GsTMx-4, indicating that Piezo1 is a crucial molecule for exercise-induced improvement of endothelial injury. Furthermore, in vitro experiments revealed that isolated mitochondria can directly respond to fluid shear stress and Yoda1. Blood flow shear stress can enhance endothelial cell mitochondrial fusion and function by activating the Piezo1-Mfn2-eNOS signaling axis.
CONCLUSION:
These findings unveil a novel mechanism by which exercise promotes endothelial cell function by increasing blood flow shear stress to activate the Piezo1-Mfn2-eNOS signaling axis, and suggest that Piezo1 may present a new target for preventing and treating hyperlipidemia-induced endothelial injury.