eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin

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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.

Love, Dominic T.Uppsala universitet,Vaskulärbiologi(Swepub:uu)domlo927 (author)
Smith, Ross O.Uppsala universitet,Vaskulärbiologi(Swepub:uu)rossm781 (author)
Hedlund, MarieUppsala universitet,Vaskulärbiologi(Swepub:uu)mimmjoha (author)
Vestweber, DietmarMax Planck Inst Mol Biomed, Münster, Germany (author)
Sessa, William C.Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA.;Yale Univ, Sch Med, Vasc Biol & Therapeut Program, New Haven, CT 06510 USA (author)
Claesson-Welsh, LenaUppsala universitet,Vaskulärbiologi(Swepub:uu)lcl04207 (author)
Uppsala universitetVaskulärbiologi (creator_code:org_t)

By the author/editor: Ninchoji, Takesh ...; Love, Dominic T.; Smith, Ross O.; Hedlund, Marie; Vestweber, Dietm ...; Sessa, William C ...; show more...; Claesson-Welsh, ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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