Functional analyses of TNFR2 in physiological and pathological retina angiogenesis.

PURPOSE To determine the function of tumor necrosis factor receptor-2 (TNFR2) in retinal development and ischemia-induced revascularization in an oxygen-induced retinopathy (OIR) model. METHODS Mice with a global deletion of TNFR2 (TNFR2-KO) or with a vascular endothelial cell (EC)-specific TNFR2 transgene (TNFR2-TG) were compared to wild-type C57BL/6 mice (WT). Retinal vasculature development was visualized by whole-mount and cross-sectional isolectin staining. In the OIR model, neonatal mice were subjected to 75% oxygen from postnatal day (P)7 to P12 and then returned to normoxia from P12 to P17. Immunostaining and biochemical analyses were performed to assess the effects of TNFR2 deletion and TNFR2 transgenesis on retinal vascular repair. RESULTS TNFR2 deletion slightly delayed, while TNFR2 transgenesis weakly promoted, intraretinal vascular development and intraretinal vessel growth. TNFR2 deletion enhanced, while TNFR2 transgene reduced, hyperoxia-induced vaso-obliteration. However, hypoxia-induced revascularization and development of deep intraretinal vessels at P17 were reduced in TNFR2-KO but increased in TNFR2-TG mice without significant increase in preretinal neovascularization (NV). Moreover, TNFR2-TG/KO mice in which only vascular EC express TNFR2 sufficiently rescued the vascular defects of TNFR2-KO in the OIR model. Biochemical analyses of retina tissues showed that the phenotypic changes in retina correlated with TNFR2-dependent activation of Nuclear factor-κB (NF-κB) survival and bone marrow kinase (Bmx)-VEGFR2 angiogenic pathways. CONCLUSIONS TNFR2 plays a marginal role during retinal vascular development. TNFR2 in vascular EC strongly prevents hyperoxia-induced vaso-obliteration by inhibiting cell apoptosis, and promotes retinal repair by enhancing hypoxia-induced revascularization without increasing pathological neovascular tufts. Therefore, activation of TNFR2 signaling may be an ideal strategy for the treatment of OIR.