Piezo1 induces endothelial responses to shear stress via soluble adenylyl Cyclase-IP3R2 circuit
Dianicha Santana Nunez,
Asrar B. Malik,
Quinn Lee,
Sang Joon Ahn,
Arnold Coctecon-Murillo,
Dana Lazarko,
Irena Levitan,
Dolly Mehta,
Yulia A. Komarova
Affiliations
Dianicha Santana Nunez
Department of Pharmacology and Regenerative Medicine, the Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL, USA
Asrar B. Malik
Department of Pharmacology and Regenerative Medicine, the Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL, USA
Quinn Lee
Department of Pharmacology and Regenerative Medicine, the Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL, USA
Sang Joon Ahn
Department of Medicine, University of Illinois College of Medicine, Chicago, IL, USA
Arnold Coctecon-Murillo
Department of Pharmacology and Regenerative Medicine, the Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL, USA
Dana Lazarko
Department of Medicine, University of Illinois College of Medicine, Chicago, IL, USA
Irena Levitan
Department of Medicine, University of Illinois College of Medicine, Chicago, IL, USA
Dolly Mehta
Department of Pharmacology and Regenerative Medicine, the Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL, USA
Yulia A. Komarova
Department of Pharmacology and Regenerative Medicine, the Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL, USA; Corresponding author
Summary: 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.
