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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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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. |
format | Online Article Text |
id | pubmed-7188482 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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