Endothelial cell Piezo1 promotes vascular smooth muscle cell differentiation on large arteries

Abstract

AbstractVascular stabilization is a mechanosensitive process, in part driven by blood flow. Here, we demonstrate the involvement of the mechanosensitive ion channel, Piezo1, in promoting arterial accumulation of vascular smooth muscle cells (vSMCs) during zebrafish development. Using a series of small molecule antagonists or agonists to temporally regulate Piezo1 activity, we identified a role for the Piezo1 channel in regulatingklf2alevels and altered targeting of vSMCs between arteries and veins. Increasing Piezo1 activity suppressedklf2aand increased vSMC association with the cardinal vein, while inhibition of Piezo1 activity increasedklf2alevels and decreased vSMC association with arteries. We supported the small molecule data within vivogenetic suppression ofpiezo1and2in zebrafish, resulting in loss oftransgelin+vSMCs on the dorsal aorta. Further, endothelial cell (EC)-specificPiezo1knockout in mice was sufficient to decrease vSMC accumulation along the descending dorsal aorta during development, thus phenocopying our zebrafish data, and supporting functional conservation of Piezo1 in mammals. To determine mechanism, we usedin vitromodeling assays to demonstrate that differential sensing of pulsatile versus laminar flow forces across endothelial cells changes the expression of mural cell differentiation genes. Together, our findings suggest a crucial role for EC Piezo1 in sensing force within large arteries to mediate mural cell differentiation and stabilization of the arterial vasculature.