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Anti-VEGFA therapeutics may aggravate hypoxia; therefore, therapy development is needed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs2\">\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Oxygen-induced retinopathy was used as a model to test the role of nitric oxide (NO) in pathological neovascularization and vessel permeability. Suppression of NO formation was achieved chemically using L-NMMA, or genetically, in endothelial NO synthase serine to alanine (S1176A) mutant mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs3\">\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Suppression of NO formation resulted in reduced retinal neoangiogenesis. Remaining vascular tufts exhibited reduced vascular leakage through stabilized endothelial adherens junctions, manifested as reduced phosphorylation of vascular endothelial (VE)-cadherin Y685 in a c-Src-dependent manner. Treatment with a single dose of L-NMMA in established retinopathy restored the vascular barrier and prevented leakage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs4\">\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>We conclude that NO destabilizes adheren junctions, resulting in vascular hyperpermeability, by converging with the VEGFA\/VEGFR2\/c-Src\/VE-cadherin pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs5\">\n                    <jats:title>Funding:<\/jats:title>\n                    <jats:p>This study was supported by the Swedish Cancer foundation (19 0119 Pj ), the Swedish Research Council (2020-01349), the Knut and Alice Wallenberg foundation (KAW 2020.0057) and a Fondation Leducq Transatlantic Network of Excellence Grant in Neurovascular Disease (17 CVD 03). KAW also supported LCW with a Wallenberg Scholar grant (2015.0275). WCS was supported by Grants R35 HL139945, P01 HL1070205, AHA MERIT Award. DV was supported by grants from the Deutsche Forschungsgemeinschaft, SFB1450, B03, and CRU342, P2.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.7554\/elife.64944","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T06:01:24Z","timestamp":1619589684000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.64944","source":"Crossref","is-referenced-by-count":51,"title":["eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin"],"prefix":"10.7554","volume":"10","author":[{"given":"Takeshi","family":"Ninchoji","sequence":"first","affiliation":[{"name":"Uppsala University, Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8530-1352","authenticated-orcid":true,"given":"Dominic T","family":"Love","sequence":"additional","affiliation":[{"name":"Uppsala 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