Role of Piezo1 mediated ER Calcium Transport in Endothelial Cell Adaptation to Shear Stress

Mechanotransduction is a key signaling mechanism by which endothelial cells (ECs) sense and adapt to mechanical forces such as pressure and shear stress. Piezo1, a mechanosensing ion channel expressed in endothelial cells (ECs), that is activated by elevated pressure and shear stress to transduce these mechanical stimuli into chemical intracellular signals. Little is known about Piezo1-downtream signaling inducing endothelial cell alignment in the directions of fluid flow, a hallmark of EC response to atheroprotective shear stress. Here, we identified a Piezo1-mediated Ca2+ comparmentalization to the endoplasmic reticulum (ER) as a major element of atheroprotective signaling. We showed that activation of Piezo1 was required and sufficient for rapid mobilization of Ca2+ to the ER lumen by sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). Activation of Piezo1 also led to transient production of cAMP by soluble Adenylyl Cyclase (sAC) and activation of Ca2+ release from cAMP-Inositol Trisphosphate Receptor 2 (IP3R2)-sensitive stores. Furthermore, We demonstrated that Piezo1 mediated ER Ca2+ release is required for ECs alignment in direction to flow and activation of atheroprotective signaling proteins such as serine-threonine protein kinase (AKT). Our results, for the first time, establish the role of Piezo1 mediated ER Ca2+ release via cAMP-IP3R2 sensitive stores as an essential signaling element ECs mechanotrasnduction.