Distal retinal ganglion cell axon transport loss and activation of p38 MAPK stress pathway following VEGF-A antagonism.
Cell Death Dis
; 7: e2212, 2016 05 05.
Article
in En
| MEDLINE
| ID: mdl-27148685
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Retinal Ganglion Cells
/
Choroidal Neovascularization
/
Vascular Endothelial Growth Factor Receptor-2
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Vascular Endothelial Growth Factor A
/
P38 Mitogen-Activated Protein Kinases
/
Diabetes Mellitus, Experimental
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Cell Death Dis
Year:
2016
Document type:
Article
Country of publication:
United kingdom