1. Cell Biology

Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin

  1. Ross Smith
  2. Takeshi Ninchoji
  3. Emma Gordon
  4. Helder André
  5. Elizabetta Dejana
  6. Dietmar Vestweber
  7. Anders Kvanta
  8. Lena Claesson-Welsh  Is a corresponding author
  1. Uppsala University, Sweden
  2. Karolinska Institute, Sweden
  3. Max Planck Institute for Molecular Biomedicine, Germany
https://doi.org/10.7554/eLife.54056
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Cite this article
  1. Ross Smith
  2. Takeshi Ninchoji
  3. Emma Gordon
  4. Helder André
  5. Elizabetta Dejana
  6. Dietmar Vestweber
  7. Anders Kvanta
  8. Lena Claesson-Welsh
(2020)
Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin
eLife 9:e54056.
https://doi.org/10.7554/eLife.54056
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Abstract

Edema stemming from leaky blood vessels is common in eye diseases such as age-related macular degeneration and diabetic retinopathy. Whereas therapies targeting vascular endothelial growth factor A (VEGFA) can suppress leakage, side-effects include vascular rarefaction and geographic atrophy. By challenging mouse models representing different steps in VEGFA/VEGF receptor 2 (VEGFR2)-induced vascular permeability, we show that targeting signaling downstream of VEGFR2 pY949 limits vascular permeability in retinopathy induced by high oxygen or by laser-wounding. Although suppressed permeability is accompanied by reduced pathological neoangiogenesis in oxygen-induced retinopathy, similarly sized lesions leak less in mutant mice, separating regulation of permeability from angiogenesis,. Strikingly, vascular endothelial (VE)-cadherin phosphorylation at the Y685, but not Y658, residue is reduced when VEGFR2 pY949 signaling is impaired. These findings support a mechanism whereby VE-cadherin Y685 phosphorylation is selectively associated with excessive vascular leakage. Therapeutically, targeting VEGFR2-regulated VE-cadherin phosphorylation could suppress edema while leaving other VEGFR2-dependent functions intact.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Text files containing the ImageJ macros used for automatic detection of microspheres in Figures 1 and 2 are provided.

Article and author information

Author details

  1. Ross Smith

    Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  2. Takeshi Ninchoji

    Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  3. Emma Gordon

    Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  4. Helder André

    Department of Clinical Neuroscience, Section for Ophthalmology and Vision, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  5. Elizabetta Dejana

    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  6. Dietmar Vestweber

    Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3517-732X

  7. Anders Kvanta

    Neuroscience, Section for Ophthalmology and Vision, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  8. Lena Claesson-Welsh

    Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
    For correspondence
    lena.welsh@igp.uu.se
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4275-2000

Funding

Australian Research Council (DE170100167)

  • Emma Gordon

Vetenskapsrådet (2015-02375)

  • Lena Claesson-Welsh

Knut och Alice Wallenbergs Stiftelse (2015.0030)

  • Lena Claesson-Welsh

Knut och Alice Wallenbergs Stiftelse (2015.0275)

  • Lena Claesson-Welsh

Fondation Leducq (17 CVD 03)

  • Lena Claesson-Welsh

Fondation ARC pour la Recherche sur le Cancer (AIRC IG 18683)

  • Elizabetta Dejana

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Mouse husbandry and oxygen-induced retinopathy (OIR) challenge took place at Uppsala University, and the University board of animal experimentation approved all animal work for those studies (Permit Number 5.8.18-06789-2018). Choroidal neovascularization (CNV) experiments took place at Karolinska Institutet, St. Erik Eye Hospital, Stockholm; the procedures were approved by the Stockholm's Committee for Ethical Animal Research (Permit Number Dnr 49/15). Animal handling was in accordance to the ARVO statement for the Use of Animals in Ophthalmologic and Vision Research.

Copyright

© 2020, Smith 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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  1. Ross Smith
  2. Takeshi Ninchoji
  3. Emma Gordon
  4. Helder André
  5. Elizabetta Dejana
  6. Dietmar Vestweber
  7. Anders Kvanta
  8. Lena Claesson-Welsh
(2020)
Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin
eLife 9:e54056.
https://doi.org/10.7554/eLife.54056

Share this article

https://doi.org/10.7554/eLife.54056

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