Deletion of p75NTR prevents vaso-obliteration and retinal neovascularization via activation of Trk- A receptor in ischemic retinopathy model

Sally L Elshaer,Azza B El-Remessy

doi:10.1038/s41598-018-30029-0

Abstract

Ischemic retinopathy is characterized by ischemia followed by retinal neovascularization (RNV) resulting in visual impairment. Given the role of neuron-secreted growth factors in regulating angiogenesis, we examined how genetic deletion of the neurotrophin receptor; p75NTR can overcome retinal ischemia using oxygen-induced retinopathy (OIR) mouse model. Wildtype (WT) or p75NTR−/− mice pups were subjected to hyperoxia (70% O2, p7-p12) then returned to normal air (relative hypoxia, p12-p17). Vascular alterations were assessed at p12 and p17 time-points. Deletion of p75NTR prevented hyperoxia-associated central vascular cell death (p12) and hypoxia-associated RNV and enhanced central vascular repair (p17). Decreased expression of apoptotic markers; preserved Akt survival signal decreased proNGF were also observed at p12. During hypoxia, deletion of p75NTR maintained VEGF and VEGFR2 activation and restored NGF/proNGF and BDNF/proBDNF levels. Deletion of p75NTR coincided with significant increases in expression and activation of NGF survival receptor, TrkA at basal and hyperoxic condition. Pharmacological inhibition of TrkA using compound K-252a (0.5 μg 1 μl−1/eye) resulted in 2-fold increase in pathological RNV and 1.34-fold increase in central vascular cell death in p75NTR−/− pups. In conclusion, deletion of p75NTR protected against retinal ischemia and prevented RNV, in part, through restoring neurotrophic support and activating TrkA receptor.

Highlights

Mice pups were subjected to hyperoxia (70% O2, p7-p12) returned to normal air
Ischemic retinopathy is characterized by an initial microvascular degeneration followed by a mal-adaptive pathological retinal neovascularization (RNV), consequent to hypoxia, in an attempt to reinstate metabolic equilibrium; that can result in visual impairment and eventually blindness[2]
In the current study using oxygen-induced retinopathy (OIR) mouse model, a standard model for ischemic retinopathy[19], we examined the impact of genetic deletion of p75NTR on vascular cell death as well as pathological neovascularization and reparative angiogenesis

Summary

Introduction

Mice pups were subjected to hyperoxia (70% O2, p7-p12) returned to normal air (relative hypoxia, p12-p17). Deletion of p75NTR coincided with significant increases in expression and activation of NGF survival receptor, TrkA at basal and hyperoxic condition. Several studies showed that NGF mediates survival and angiogenic signal through activation of its high affinity; TrkA receptor[7,8,9]. Few reports showed that proNGF-mediated angiogenic behavior in breast cancer cells[17] and retinal endothelial cells[18] that was regulated through activation of TrkA but not p75NTR. Our group observed that inhibition of p75NTR was associated with enhanced TrkA activation[18], suggesting a cross-talk between p75NTR expression and TrkA activation Despite these significant findings, there is gap in knowledge about the interplay between NGF and proNGF and their receptors p75NTR and TrkA in response to hypoxia and angiogenesis

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