TY - JOUR T1 - eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin JF - bioRxiv DO - 10.1101/2020.11.24.396077 SP - 2020.11.24.396077 AU - Takeshi Ninchoji AU - Dominic T. Love AU - Ross O. Smith AU - Marie Hedlund AU - Dietmar Vestweber AU - William C. Sessa AU - Lena Claesson-Welsh Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/11/24/2020.11.24.396077.abstract N2 - Hypoxia and the production of vascular endothelial growth factor A (VEGFA) promote blood vessel leakiness and edema in ocular diseases. Therapeutics targeting VEGFA suppress leakiness and edema but aggravate hypoxia; therefore, new therapeutics are needed. We examined the role of endothelial nitric oxide synthase (eNOS) in pathological neovascularization and vessel permeability during oxygen-induced retinopathy. NO formation was suppressed chemically using L-NMMA, or genetically, in eNOS serine to alanine (S1176A) mutant mice, resulting in reduced retinal neoangiogenesis. Both strategies resulted in reduced vascular leakage by stabilizing endothelial adherens junctions through suppressed phosphorylation of vascular endothelial (VE)-cadherin Y685 in a c-Src-dependent manner. Intervention treatment by a single dose of L-NMMA in established retinopathy restored the vascular barrier and prevented leakage. We conclude that eNOS induces destabilization of adherens junctions and vascular hyperpermeability by converging with the VEGFA/VEGFR2/c-Src/VE-cadherin pathway and that this pathway can be selectively inhibited by blocking NO formation.eNOSendothelial nitric oxide synthaseL-NMMANω-Methyl-L-arginine acetateNos3gene designation for murine endothelial nitric oxide synthase 3OIRoxygen-induced retinopathyPLAproximity ligation assayVEGFAvascular endothelial growth factor AVE-cadherinvascular endothelial-cadherin ER -