{"doi":"10.7554/elife.64944","title":"eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin","abstract":"Background: Hypoxia and consequent production of vascular endothelial growth factor A (VEGFA) promote blood vessel leakiness and edema in ocular diseases. Anti-VEGFA therapeutics may aggravate hypoxia; therefore, therapy development is needed. Methods: 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. Results: 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. Conclusions: We conclude that NO destabilizes adheren junctions, resulting in vascular hyperpermeability, by converging with the VEGFA/VEGFR2/c-Src/VE-cadherin pathway. Funding: 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.","journal":"eLife","year":2021,"id":156932,"datarank":1.6108694526471754,"base_score":3.970291913552122,"endowment":3.970291913552122,"self_citation_contribution":0.5955437870328184,"citation_network_contribution":1.015325665614357,"self_endowment_contribution":0.5955437870328184,"citer_contribution":1.015325665614357,"corpus_percentile":null,"corpus_rank":null,"citation_count":52,"citer_count":50,"citers_with_citation_signal":40,"citers_with_endowment":40,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9667,"is_data_producer":true,"deposit_databanks":{"Dryad":["10.5061/dryad.x69p8czhv"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":662926,"name":"Dominic Love","orcid":"0000-0001-8530-1352","position":1,"is_corresponding":false},{"id":662927,"name":"Ross Smith","orcid":"0000-0003-4239-3204","position":2,"is_corresponding":false},{"id":663962,"name":"Marie Hedlund","orcid":null,"position":3,"is_corresponding":false},{"id":262886,"name":"Dietmar Vestweber","orcid":"0000-0002-3517-732X","position":4,"is_corresponding":false},{"id":328610,"name":"William C. Sessa","orcid":"0000-0001-5759-1938","position":5,"is_corresponding":false},{"id":110372,"name":"Lena Claesson‐Welsh","orcid":"0000-0003-4275-2000","position":6,"is_corresponding":false},{"id":662925,"name":"Takeshi Ninchoji","orcid":"0000-0001-7590-1522","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-18T23:44:17.471040Z","pmid":"33908348","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}