PIEZO1 Mediates Apoptosis of Endothelial Cells via Enhancing HMGA2 Expression Under Simulated Microgravity

Exposure to microgravity results in cardiovascular deconditioning, with endothelial cell apoptosis recognized as a pivotal initiating event. However, the mechanosensitive mechanisms underlying this process remain poorly understood. Here, we demonstrate that the expression of mechanosensitive ion channel protein PIEZO1 is upregulated in human umbilical vein endothelial cells (HUVECs) under simulated microgravity. Functional studies revealed that PIEZO1 activation promotes endothelial apoptosis under simulated microgravity conditions. Proteomic analysis following PIEZO1 knockdown revealed extensive alterations in biological processes associated with apoptosis. Furthermore, we found that PIEZO1 activation triggers calcium influx, leading to elevated expression of the HMGA2. Moreover, we identify that PIEZO1 activation induces calcium influx, which subsequently elevates the expression of HMGA2. The knockdown of HMGA2 significantly mitigated microgravity-induced endothelial apoptosis, indicating its role in PIEZO1-mediated apoptosis. These findings reveal a novel PIEZO1–Ca2+–HMGA2 axis critical for microgravity-induced endothelial apoptosis, providing mechanistic insight into cardiovascular adaptation to spaceflight and potential therapeutic targets for countermeasure development.