Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells
Abstract
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 Ca2+-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, g-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.
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Source data files have been provided for all 11 data Figures and indicated as such in each relevant figure legend.
Article and author information
Author details
Funding
Wellcome (110044/Z/15/Z)
- David J Beech
British Heart Foundation (RG/17/11/33042)
- David J Beech
European Commission (H2020-MSCA-IF-2016 SAVE 748369)
- Vincenza Caolo
Fonds Wetenschappelijk Onderzoek (G091018N)
- Elizabeth AV Jones
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal use was authorized by the University of Leeds Animal Ethics Committee and Home Office UK (Project Licence P606320FB to David J Beech).
Copyright
© 2020, Caolo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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