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Nicholas Sitaras, H. Uri Saragovi, Sylvain Chemtob, Przemyslaw Sapieha; Pro-NGF induces endothelial cell death via the P75 neurotrophin receptor (P75NTR) in a mouse model of oxygen-induced retinopathy (OIR). Invest. Ophthalmol. Vis. Sci. 2013;54(15):6346.
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Proliferative Retinopathies (PRs) are the major cause of blindness in working-age and pediatric populations. These diseases are characterized by an initial microvascular dropout followed by a disparate compensatory albeit excessive and pathological vascularization leading to blinding tractional retinal detachment. Neurotrophins, or the lack thereof, have previously been shown to contribute to the pathogenesis of PRs. Particularly, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) can either stimulate or inhibit angiogenesis in the retina in both developmental and pathological contexts. This discrepancy may be accounted by the presence of neurotrophic precursor forms that preferentially bind to the low-affinity P75 neurotrophin receptor (P75NTR). Here we explored the expression patterns of neurotrophin precursors and their low-affinity receptor, P75NTR and determined their role in the PRs.
P75NTR and pro-NGF expression were measured in whole mouse retinas by western blot and immunohistochemistry. Retinal angiogenesis was appreciated following in vivo intravitreal injections of selective antagonists of pro-NGF or P75NTR in C57Bl6 mice exposed to a model of oxygen-induced retinopathy (OIR) which loosely mimics PRs (75% O2 from post natal day 7 [P7] to P12). Expression profiles of pro- and anti-angiogenic genes were assessed in whole retinas following treatment with antagonist injection.
Our data demonstrates preferential expression of P75NTR in Müller glia and astrocytes. In OIR, P75NTR levels increased slightly during the neovascularization (NV) phase (P12-P17), whereas accumulation of pro-NGF was detected during vaso-obliteration (VO) and during NV. Inhibition of P75NTR during hyperoxic exposure significantly reduced VO at P12. This reduction in VO secondary to inhibition of P75NTR during the hyperoxic phase was associated with a decrease in tumor-necrosis factor-α (TNF-α). In contrast, antagonism of P75NTR did not impede/exacerbate pathological neovascularization (NV).
This study highlights the novel role of P75NTR in a retinal vasculopathy. Induction of pro-NGF during the early phases of hyperoxia-induced vaso-obliteration, activates P75NTR and provokes endothelial cell death. These results introduce potential therapeutic targets, namely P75NTR or pro-NGF, for the treatment of PRs.
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