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Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling

  1. Claudio A Franco
  2. Martin L Jones
  3. Miguel O Bernabeu
  4. Anne-Clemence Vion
  5. Pedro Barbacena
  6. Jieqing Fan
  7. Thomas Mathivet
  8. Catarina G Fonseca
  9. Anan Ragab
  10. Terry P Yamaguchi
  11. Peter V Coveney
  12. Richard A Lang
  13. Holger Gerhardt  Is a corresponding author
  1. London Research Institute, United Kingdom
  2. The University of Edinburgh, United Kingdom
  3. Faculdade de Medicina Universidade de Lisboa, Portugal
  4. Cincinnati Children's Hospital Medical Center, United States
  5. Vesalius Research Center, Belgium
  6. National Institutes of Health, United States
  7. University College London, United Kingdom
Research Article
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Cite this article as: eLife 2016;5:e07727 doi: 10.7554/eLife.07727

Abstract

Endothelial cells respond to molecular and physical forces in development and vascular homeostasis. Deregulation of endothelial responses to flow-induced shear is believed to contribute to many aspects of cardiovascular diseases including atherosclerosis. However, how molecular signals and shear-mediated physical forces integrate to regulate vascular patterning is poorly understood. Here we show that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/Wnt11 renders endothelial cells more sensitive to shear, resulting in axial polarization and migration against flow at lower shear levels. Integration of flow modelling and polarity analysis in entire vascular networks demonstrates that polarization against flow is achieved differentially in artery, vein, capillaries and the primitive sprouting front. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus.

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Author details

  1. Claudio A Franco

    Vascular Biology Laboratory, London Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Martin L Jones

    Vascular Biology Laboratory, London Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Miguel O Bernabeu

    Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Anne-Clemence Vion

    Vascular Biology Laboratory, London Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Pedro Barbacena

    Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal
    Competing interests
    The authors declare that no competing interests exist.

  6. Jieqing Fan

    The Visual Systems Group, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Thomas Mathivet

    Vascular Patterning Laboratory, Vesalius Research Center, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  8. Catarina G Fonseca

    Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal
    Competing interests
    The authors declare that no competing interests exist.

  9. Anan Ragab

    Vascular Biology Laboratory, London Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  10. Terry P Yamaguchi

    Cancer and Developmental Biology Laboratory, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Peter V Coveney

    Centre for Computational Science, Department of Chemistry, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  12. Richard A Lang

    The Visual Systems Group, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.

  13. Holger Gerhardt

    Vascular Biology Laboratory, London Research Institute, London, United Kingdom
    For correspondence
    holger.gerhardt@mdc-berlin.de
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: Animal procedures were performed in accordance with the United Kingdom Home Office Animal Act 1986 under the authority of project license PPL 80/2391.

Reviewing Editor

  1. Ewa Paluch, University College London, United Kingdom

Publication history

  1. Received: March 26, 2015
  2. Accepted: February 3, 2016
  3. Accepted Manuscript published: February 4, 2016 (version 1)
  4. Version of Record published: March 11, 2016 (version 2)

Copyright

© 2016, Franco 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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