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

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 cha...

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Autores principales: Smith, Ross O, Ninchoji, Takeshi, Gordon, Emma, André, Helder, Dejana, Elisabetta, Vestweber, Dietmar, Kvanta, Anders, Claesson-Welsh, Lena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188482/
https://www.ncbi.nlm.nih.gov/pubmed/32312382
http://dx.doi.org/10.7554/eLife.54056
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author Smith, Ross O
Ninchoji, Takeshi
Gordon, Emma
André, Helder
Dejana, Elisabetta
Vestweber, Dietmar
Kvanta, Anders
Claesson-Welsh, Lena
author_facet Smith, Ross O
Ninchoji, Takeshi
Gordon, Emma
André, Helder
Dejana, Elisabetta
Vestweber, Dietmar
Kvanta, Anders
Claesson-Welsh, Lena
author_sort Smith, Ross O
collection PubMed
description 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.
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spelling pubmed-71884822020-04-29 Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin Smith, Ross O Ninchoji, Takeshi Gordon, Emma André, Helder Dejana, Elisabetta Vestweber, Dietmar Kvanta, Anders Claesson-Welsh, Lena eLife Cell Biology 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. eLife Sciences Publications, Ltd 2020-04-21 /pmc/articles/PMC7188482/ /pubmed/32312382 http://dx.doi.org/10.7554/eLife.54056 Text en © 2020, Smith et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Smith, Ross O
Ninchoji, Takeshi
Gordon, Emma
André, Helder
Dejana, Elisabetta
Vestweber, Dietmar
Kvanta, Anders
Claesson-Welsh, Lena
Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin
title Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin
title_full Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin
title_fullStr Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin
title_full_unstemmed Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin
title_short Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin
title_sort vascular permeability in retinopathy is regulated by vegfr2 y949 signaling to ve-cadherin
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188482/
https://www.ncbi.nlm.nih.gov/pubmed/32312382
http://dx.doi.org/10.7554/eLife.54056
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