期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 182, 期 4, 页码 1379-1390出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2012.12.032
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资金
- Medical Research Council [G0901303]
- Medical Research Council Dorothy Hodgkin Postgraduate Award
- Helen Hamlyn Trust
- Fight for Sight
- National Institute for Health Research Biomedical Research Centre Moorfields
- University College London Institute of Ophthalmology
- MRC [G0800946, G0901303] Funding Source: UKRI
- Medical Research Council [G0800946, G0901303] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10101] Funding Source: researchfish
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.
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