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 mechanosen-sitive channel Piezo1 by defined shear forces induces Ca2+ entry into the endo-plasmic 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 ad-enylyl 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. Over -expression of constitutively active Akt1 restores the shear-induced alignment of ECs lacking Piezo1 or IP3R2, as well as the flow-induced vasodilation in endothe-lial 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.