title: Distal retinal ganglion cell axon transport loss and activation of p38 MAPK stress pathway following VEGF-A antagonism.
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.
authors.affiliation: Department of Ocular Biology and Therapeutics, University College London, Institute of Ophthalmology, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Foxton
authors.affiliation: John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Osborne
authors.affiliation: John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.|Wellcome Trust Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.|Cambridge NIHR Biomedical Research Centre, Cambridge, UK.|Eye Department, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: K R
authors.initials: KR
authors.lastname: Martin
authors.affiliation: Department of Ocular Biology and Therapeutics, University College London, Institute of Ophthalmology, London, UK.|The Schepens Eye Research Institute and Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Ng
authors.affiliation: Department of Ocular Biology and Therapeutics, University College London, Institute of Ophthalmology, London, UK.
authors.forename: D T
authors.initials: DT
authors.lastname: Shima
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001370:Axonal Transport / Q000187:drug effects; D058948:Cell Tracking; D002772:Cholera Toxin / Q000737:chemistry / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D058449:Intravitreal Injections; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000008:administration & dosage / Q000009:adverse effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D055551:HSP27 Heat-Shock Proteins; C486699:Hspb2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D002772:Cholera Toxin; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D048051:p38 Mitogen-Activated Protein Kinases