Distal retinal ganglion cell axon transport loss and activation of p38 MAPK stress pathway following VEGF-A antagonism.

R Foxton,A Osborne,Y-S Ng,K R Martin,D T Shima

doi:10.1038/cddis.2016.110

R Foxton, A Osborne + Show 3 more

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https://doi.org/10.1038/cddis.2016.110

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Abstract

There is increasing evidence that VEGF-A antagonists may be detrimental to neuronal health following ocular administration. Here we investigated firstly the effects of VEGF-A neutralization on retinal neuronal survival in the Ins2Akita diabetic and JR5558 spontaneous choroidal neovascularization (CNV) mice, and then looked at potential mechanisms contributing to cell death. We detected elevated apoptosis in the ganglion cell layer in both these models following VEGF-A antagonism, indicating that even when vascular pathologies respond to treatment, neurons are still vulnerable to reduced VEGF-A levels. We observed that retinal ganglion cells (RGCs) seemed to be the cells most susceptible to VEGF-A antagonism, so we looked at anterograde transport in these cells, due to their long axons requiring optimal protein and organelle trafficking. Using cholera toxin B-subunit tracer studies, we found a distal reduction in transport in the superior colliculus following VEGF-A neutralization, which occurred prior to net RGC loss. This phenomenon of distal transport loss has been described as a feature of early pathological changes in glaucoma, Alzheimer's and Parkinson's disease models. Furthermore, we observed increased phosphorylation of p38 MAPK and downstream Hsp27 stress pathway signaling in the retinas from these experiments, potentially providing a mechanistic explanation for our findings. These experiments further highlight the possible risks of using VEGF-A antagonists to treat ocular neovascular disease, and suggest that VEGF-A may contribute to the maintenance and function of axonal transport in neurons of the retina.

Highlights

VEGF-A was initially named following discovery of its potent effects on endothelium
We observed that retinal ganglion cells (RGCs) seemed to be the cells most susceptible to VEGF-A antagonism, so we looked at anterograde transport in these cells, due to their long axons requiring optimal protein and organelle trafficking
VEGF-A is neurogenic and neuroprotective in a variety of different cell types, in vitro and in vivo.[2,3,4,5]. These findings raised the possibility that blocking VEGF-A when treating neovascular disease could adversely deprive neurons of an essential survival factor. We initially investigated this in models of ischemia– reperfusion injury,[6] ocular hypertension (OHT), to parallel a disease scenario where VEGF-A antagonists are used in the clinic, namely for neovascular glaucoma, or as an adjunct to trabeculectomy surgery.[7]

Summary

Introduction

VEGF-A was initially named following discovery of its potent effects on endothelium. contrary to its 'vascular'specific title, VEGF-A acts on multiple tissues, including in the nervous system. VEGF-A is neurogenic and neuroprotective in a variety of different cell types, in vitro and in vivo.[2,3,4,5] These findings raised the possibility that blocking VEGF-A when treating neovascular disease could adversely deprive neurons of an essential survival factor We initially investigated this in models of ischemia– reperfusion injury,[6] ocular hypertension (OHT), to parallel a disease scenario where VEGF-A antagonists are used in the clinic, namely for neovascular glaucoma, or as an adjunct to trabeculectomy surgery.[7] We found in both models that exogenously injected VEGF-A was protective, and. Received 05.11.15; revised 04.3.16; accepted 16.3.16; Edited by G Melino accelerate neuronal apoptosis in these models, findings that may have implications for treating ocular neovascular disease with anti-VEGF drugs

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