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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.<\/jats:p>","DOI":"10.7554\/elife.54056","type":"journal-article","created":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T20:06:22Z","timestamp":1587413182000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.54056","source":"Crossref","is-referenced-by-count":101,"title":["Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4239-3204","authenticated-orcid":true,"given":"Ross O","family":"Smith","sequence":"first","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory Uppsala University, Uppsala, 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