Piezo1 channel activates ADAM10 sheddase to regulate Notch1 and gene expression

Abstract

Mechanical force has emerged as a determinant of Notch signalling but the mechanisms of force sensing and coupling to Notch are unclear. Here we propose a role for Piezo1 channels, the recently identified mechanosensors of mammalian systems. Piezo1 channel opening in response to shear stress or a chemical agonist led to activation of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a Ca 2+ -regulated transmembrane sheddase that mediates S2 Notch1 cleavage. Consistent with this observation there was increased Notch1 intracellular domain (NICD) that depended on ADAM10 and the downstream S3 cleavage enzyme, -secretase. Endothelial-specific disruption of Piezo1 in mice led to decreased Notch1-regulated gene expression in hepatic vasculature, consistent with prior evidence that Notch1 controls hepatic perfusion. The data suggest Piezo1 as a mechanism for coupling physiological force at the endothelium to ADAM10, Notch1, gene expression and vascular function.

Force Sensing by Piezo Channels in Cardiovascular Health and Disease

“…Genetic deletion of Piezo1 abolishes Yoda1 effects, 21,27,75,112 and Piezo1 knockdown by RNA interference suppresses such effects. 7,28,30,59,62,73,74 Yoda1 is not without limitations, which include poor aqueous solubility at greater than ≈20 μM. 106 Nevertheless, despite the need for caution and chemical refinement, Yoda1 is a valuable tool compound.…”

Emerging role of Piezo ion channels in cardiovascular development

“…Calpain has been displayed to regulate the differentiation of MSCs lineage cells, such as myoblasts 55 . Stress induced opening of Piezo channels also activates a disintegrin and metalloproteinase domain -containing protein 10 (ADAM10) sheddase and regulates the Notch1 signaling 56 . Notch signaling is the most established pathway regulating the differentiation and proliferation of progenitor cells and stem cells in short range 57 .…”

“…52 Stress induced opening of Piezo channels also activates a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) sheddase and regulates the Notch1 signaling. 53 Notch signaling is the most established pathway regulating the differentiation and proliferation of progenitor cells and stem cells in short range. 54 ADAM10 dependent Notch1 and Notch4 have been shown to control vascular bed development in mice.…”