Piezo1 induces endothelial responses to shear stress via soluble adenylyl Cyclase-IPR2 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 Ca entry into the endoplasmic reticulum (ER) via the ER Ca ATPase pump. This entry is followed by inositol trisphosphate receptor 2 (IPR2)-elicited ER Ca release into the cytosol. The mechanism of ER Ca release involves the generation of cAMP by soluble adenylyl cyclase (sAC), leading to IPR2-evoked Ca gating. Depleting sAC or IPR2 prevents ER Ca 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 IPR2, as well as the flow-induced vasodilation in endothelial restricted Piezo1 knockout mice. These studies describe an unknown Piezo1-cAMP-IPR2 circuit as an essential mechanism activating Akt signaling and inducing adaptive changes in ECs to laminar flow.