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.

Automated summary

Endothelial cells sense shear stress through Piezo1 and activate ER Ca2+ entry and release via IP3R2. The involvement of sAC and IP3R2 in this process is crucial.