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

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.

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

  • 4,636
    views
  • 1,400
    downloads
  • 126
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  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
(2016)
Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling
eLife 5:e07727.
https://doi.org/10.7554/eLife.07727

Share this article

https://doi.org/10.7554/eLife.07727

Further reading

    1. Cell Biology
    2. Immunology and Inflammation
    Alejandro Rosell, Agata Adelajda Krygowska ... Esther Castellano Sanchez
    Research Article

    Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.

    1. Cell Biology
    2. Genetics and Genomics
    Keva Li, Nicholas Tolman ... UK Biobank Eye and Vision Consortium
    Research Article

    A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.