Piezo1 induces endothelial responses to shear stress via soluble adenylyl Cyclase-IP₃R2 circuit

Endothelial cells (ECs) continuously sense and adapt to changes in shear stress generated by blood flow. Here, we show that the activation of the mechanosensitive channel Piezo1 by defined shear forces induces Ca²⁺ entry into the endoplasmic reticulum (ER) via the ER Ca²⁺ ATPase pump. This entry is followed by inositol trisphosphate receptor 2 (IP₃R2)-elicited ER Ca²⁺ release into the cytosol. The mechanism of ER Ca²⁺ release involves the generation of cAMP by soluble adenylyl cyclase (sAC), leading to IP₃R2-evoked Ca²⁺ gating. Depleting sAC or IP₃R2 prevents ER Ca²⁺ release and blocks EC alignment in the direction of flow. Overexpression of constitutively active Akt1 restores the shear-induced alignment of ECs lacking Piezo1 or IP₃R2, as well as the flow-induced vasodilation in endothelial restricted Piezo1 knockout mice. These studies describe an unknown Piezo1-cAMP-IP₃R2 circuit as an essential mechanism activating Akt signaling and inducing adaptive changes in ECs to laminar flow.