1. Cell Biology
  2. Developmental Biology
Download icon

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
  • Cited 63
  • Views 4,233
  • Annotations
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.

Article and author information

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.

Metrics

  • 4,233
    Page views
  • 1,241
    Downloads
  • 63
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Asha Mary Joseph et al.
    Research Article

    Translesion synthesis (TLS) is a highly conserved mutagenic DNA lesion tolerance pathway, which employs specialized, low-fidelity DNA polymerases to synthesize across lesions. Current models suggest that activity of these polymerases is predominantly associated with ongoing replication, functioning either at or behind the replication fork. Here we provide evidence for DNA damage-dependent function of a specialized polymerase, DnaE2, in replication-independent conditions. We develop an assay to follow lesion repair in non-replicating Caulobacter and observe that components of the replication machinery localize on DNA in response to damage. These localizations persist in the absence of DnaE2 or if catalytic activity of this polymerase is mutated. Single-stranded DNA gaps for SSB binding and low-fidelity polymerase-mediated synthesis are generated by nucleotide excision repair, as replisome components fail to localize in the absence of NER. This mechanism of gap-filling facilitates cell cycle restoration when cells are released into replication-permissive conditions. Thus, such cross-talk (between activity of NER and specialized polymerases in subsequent gap-filling) helps preserve genome integrity and enhances survival in a replication-independent manner.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Marzia Munafò et al.
    Research Article

    The Nuclear Pore Complex (NPC) is the principal gateway between nucleus and cytoplasm that enables exchange of macromolecular cargo. Composed of multiple copies of ~30 different nucleoporins (Nups), the NPC acts as a selective portal, interacting with factors which individually license passage of specific cargo classes. Here we show that two Nups of the inner channel, Nup54 and Nup58, are essential for transposon silencing via the PIWI-interacting RNA (piRNA) pathway in the Drosophila ovary. In ovarian follicle cells, loss of Nup54 and Nup58 results in compromised piRNA biogenesis exclusively from the flamenco locus, whereas knockdowns of other NPC subunits have widespread consequences. This provides evidence that some nucleoporins can acquire specialised roles in tissue-specific contexts. Our findings consolidate the idea that the NPC has functions beyond simply constituting a barrier to nuclear/cytoplasmic exchange, as genomic loci subjected to strong selective pressure can exploit NPC subunits to facilitate their expression.