Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells

• Published in: eLife Vol. 9
• Main Authors: Caolo, Vincenza, Debant, Marjolaine, Endesh, Naima, Futers, T Simon, Lichtenstein, Laeticia, Bartoli, Fiona, Parsonage, Gregory, Jones, Elizabeth Av, Beech, David J
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 02-06-2020; eLife Sciences Publications, Ltd
• Subjects: ADAM10 Protein - metabolism; Amyloid Precursor Protein Secretases - metabolism; Animals; Antibodies; Calcium; Cell activation; Cell Biology; Cells, Cultured; endothelial cell; Endothelial cells; Endothelial Cells - metabolism; Enzyme Activation; Experiments; Gene Expression Regulation; Humans; ion channel; Ion Channels - antagonists & inhibitors; Ion Channels - metabolism; Ligands; Male; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Microvasculature; notch signalling; Notch1 protein; Protein Domains; proteinase; Receptor, Notch1 - metabolism; Roles; Secretase; Sensors; Shear stress; Statistical analysis; Stress, Mechanical; Transcription activation; Transcription Factor HES-1 - genetics; mouse; cell biology; proteinase; ion channel; endothelial cell; notch signalling; human
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.50684

Mechanical force is a determinant of Notch signalling but the mechanism of force detection and its coupling to Notch are unclear. We propose a role for Piezo1 channels, which are mechanically-activated non-selective cation channels. In cultured microvascular endothelial cells, Piezo1 channel activation by either shear stress or a chemical agonist Yoda1 activated a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a Ca
-regulated transmembrane sheddase that mediates S2 Notch1 cleavage. Consistent with this observation, we found Piezo1-dependent increase in the abundance of Notch1 intracellular domain (NICD) that depended on ADAM10 and the downstream S3 cleavage enzyme, γ-secretase. Conditional endothelial-specific disruption of Piezo1 in adult mice suppressed the expression of multiple Notch1 target genes in hepatic vasculature, suggesting constitutive functional importance in vivo. The data suggest that Piezo1 is a mechanism conferring force sensitivity on ADAM10 and Notch1 with downstream consequences for sustained activation of Notch1 target genes and potentially other processes.