title: VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma.
abstract: Vascular endothelial growth factor A (VEGF-A) is a validated therapeutic target in several angiogenic- and vascular permeability-related pathological conditions, including certain cancers and potentially blinding diseases, such as age-related macular degeneration and diabetic retinopathy. We and others have shown that VEGF-A also plays an important role in neuronal development and neuroprotection, including in the neural retina. Antagonism of VEGF-A function might therefore present a risk to neuronal survival as a significant adverse effect. Herein, we demonstrate that VEGF-A acts directly on retinal ganglion cells (RGCs) to promote survival. VEGF receptor-2 signaling via the phosphoinositide-3-kinase/Akt pathway was required for the survival response in isolated RGCs. These results were confirmed in animal models of staurosporine-induced RGC death and experimental hypertensive glaucoma. Importantly, we observed that VEGF-A blockade significantly exacerbated neuronal cell death in the hypertensive glaucoma model. Our findings highlight the need to better define the risks associated with use of VEGF-A antagonists in the ocular setting.
authors: National Institute for Health Research, Biomedical Research Centre Moorfields Eye Hospital.
authors: Richard H
authors: RH
authors: Foxton
authors: Arthur
authors: A
authors: Finkelstein
authors: Sauparnika
authors: S
authors: Vijay
authors: Annegret
authors: A
authors: Dahlmann-Noor
authors: Peng T
authors: PT
authors: Khaw
authors: James E
authors: JE
authors: Morgan
authors: David T
authors: DT
authors: Shima
authors: Yin-Shan
authors: YS
authors: Ng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D005901:Glaucoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D039921:Neuropilins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009500:Neutralization Tests; D009798:Ocular Hypertension / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D023382:Toxicity Tests, Acute; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D039921:Neuropilins; D018696:Neuroprotective Agents; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases