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Cell Death Dis. 2016 May 5;7:e2212. doi: 10.1038/cddis.2016.110.

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

Author information

1
Department of Ocular Biology and Therapeutics, University College London, Institute of Ophthalmology, London, UK.
2
John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
3
Wellcome Trust Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
4
Cambridge NIHR Biomedical Research Centre, Cambridge, UK.
5
Eye Department, Addenbrooke's Hospital, Cambridge, UK.
6
The Schepens Eye Research Institute and Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.

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 Ins2(Akita) 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.

PMID:
27148685
PMCID:
PMC4917649
DOI:
10.1038/cddis.2016.110
[Indexed for MEDLINE]
Free PMC Article

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