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

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Cite this article as: eLife 2020;9:e50684 doi: 10.7554/eLife.50684

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

  1. Vincenza Caolo

    Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Marjolaine Debant

    Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5988-3395
  3. Naima Endesh

    Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. T Simon Futers

    Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Laeticia Lichtenstein

    Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3900-786X
  6. Fiona Bartoli

    School of Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Gregory Parsonage

    Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Elizabeth AV Jones

    Cardiovascular Sciences, KU Leuven, Leuven, Belgium
    For correspondence
    liz.jones@kuleuven.be
    Competing interests
    The authors declare that no competing interests exist.
  9. David J Beech

    Medicine, University of Leeds, Leeds, United Kingdom
    For correspondence
    d.j.beech@leeds.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7683-9422

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).

Reviewing Editor

  1. Karina Yaniv, Weizmann Institute of Science, Israel

Publication history

  1. Received: July 30, 2019
  2. Accepted: June 1, 2020
  3. Accepted Manuscript published: June 2, 2020 (version 1)
  4. Version of Record published: June 15, 2020 (version 2)

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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