Shear Stress‐Stimulated Trafficking of Endothelial Piezo1 to Splenic Capsule Boosts Spleen Contraction and Exercise Endurance

ABSTRACT Haemodynamic shear stress, sensed by vascular endothelial cells (ECs), is crucial for the functional integrity of ECs and the systemic benefits of exercise. Here, we observed that shear stress triggers the release of medium/large extracellular vesicles (m/lEVs), from ECs via activation of the mechanosensitive ion channel Piezo1. Endothelial Piezo1 activation induces Piezo1 translocation to the cell periphery, facilitating its trafficking from the vascular ECs to the smooth muscle cells in the splenic capsule. Within the splenic capsule, the translocated Piezo1 acts as a downstream effector of α1‐adrenergic receptor, boosting exercise‐induced spleen contraction and enhancing exercise endurance. Genetic or pharmacological inhibition of Piezo1 trafficking from ECs impaired spleen contraction during exercise and reduced exercise endurance in mice. Additionally, exercise‐induced m/lEV release contributes to safeguard endothelial function through modulating intracellular Piezo1 homeostasis. Furthermore, positive correlations between exercise‐induced increases in circulating Piezo1‐enriched m/lEVs and the degree of spleen contraction were also observed in human volunteers. These findings unveil a vasculo‐splenic axis during exercise, in which EC‐derived m/lEVs shuttle Piezo1 to maintain endothelial function and exercise endurance, highlighting a novel role of Piezo1 in inter‐organ communication.