Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin
- Uppsala University, Sweden
- Karolinska Institute, Sweden
- Max Planck Institute for Molecular Biomedicine, Germany
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
Lena Claesson-Welsh
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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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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