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
Share this article
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
  2. Download BibTeX
  3. Download .RIS

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.

Metrics

  • 4,067
    views
  • 606
    downloads
  • 85
    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. 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

Categories and tags

Research organism

Further reading

    1. Cell Biology

    Small-molecule activation of TFEB alleviates Niemann–Pick disease type C via promoting lysosomal exocytosis and biogenesis

    Kaili Du, Hongyu Chen ... Dan Li
    Research Article

    Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

    1. Cell Biology

    Stratification of enterochromaffin cells by single-cell expression analysis

    Yan Song, Linda J Fothergill ... Gene W Yeo
    Research Article

    Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify 14 EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic, and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.

    1. Cell Biology
    2. Developmental Biology

    Lens Development: Bringing signaling complexity into focus

    Sarah Y Coomson, Salil A Lachke
    Insight

    A study in mice reveals key interactions between proteins involved in fibroblast growth factor signaling and how they contribute to distinct stages of eye lens development.