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Hossein Ameri, Jun Wang, Ronald G. Tilton, Bernard F. Godley, Wenbo Zhang; Tweak/fn14 Pathway Is A Novel Mediator Of Neovascularization During Ischemic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2555. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal neovascularization is a major cause of blindness in proliferative diabetic retinopathy and retinopathy of prematurity. The interaction between tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 is implicated in angiogenesis but the specific role of TWEAK/Fn14 in retinal diseases is completely unknown. The goal of this study was to test whether TWEAK/Fn14 is required for retinal neovascularization during ischemic retinopathy.
Oxygen-induced ischemic retinopathy (OIR) was produced by maintaining C57BL/6 wild type neonatal mice in 75% oxygen from postnatal day (P)7 to P12 and room air from P12 to P17. Control mice were kept in room air. Retinas were prepared for analysis of mRNA for TWEAK and Fn14 by quantitative PCR. The interaction of TWEAK and Fn14 was blocked by intravitreal injection of a soluble Fn14-Fc decoy receptor (2.5 μg/eye) at P12. The retinal vasculature was examined at P17 by fluorescence microscopy after labeling retinal whole mounts with isolectin-B4.
At P12 after pups were exposed to hyperoxia for 5 days, there was no change in retinal levels of Fn14 and TWEAK mRNA vs control retinas. Fn14 mRNA remained constant in control mice from P12 to P17. However, the level of Fn14 was markedly increased at P13 in OIR mice and maintained at high level (~ 3 fold vs control) until P17. TWEAK mRNA was increased in control mice from P12 to P17 but OIR did not increase it further. Treatment with Fn14-Fc decoy receptor substantially reduced retinal neovascularization during ischemic retinopathy.
These findings suggest that the TWEAK/Fn14 pathway is upregulated and is critically involved in the initiation and progression of retinal neovascularization during ischemic retinopathy.
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