eNOS/NO and their role in modifying the vascular barrier in retinopathy - Source data

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 (eNOS) 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, indicated by 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. Conclusion: We conclude that NO destabilizes adherens 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 01 H), 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.