Antioxidant or neurotrophic factor treatment preserves function in a mouse model of neovascularization-associated oxidative stress

• Published in: The Journal of clinical investigation Vol. 119; no. 3; pp. 611 - 623
• Main Authors: Dorrell, Michael I, Aguilar, Edith, Jacobson, Ruth, Yanes, Oscar, Gariano, Ray, Heckenlively, John, Banin, Eyal, Ramirez, G Anthony, Gasmi, Mehdi, Bird, Alan, Siuzdak, Gary, Friedlander, Martin
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2009
• Subjects: Angiogenesis; Angiogenesis Inhibitors - therapeutic use; Animals; Antioxidants; Antioxidants - metabolism; Antioxidants - pharmacology; Antioxidants - therapeutic use; Aptamers, Nucleotide - therapeutic use; Biomedical research; Blood vessels; Care and treatment; Cell death; Disease; Disease Models, Animal; Electroretinography; Gene Expression - genetics; Gene Expression Profiling; Gene Transfer Techniques; Genotype & phenotype; Health aspects; Lipid Peroxidation - physiology; Macular degeneration; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Growth Factors - genetics; Nerve Growth Factors - metabolism; Nerve Growth Factors - therapeutic use; Neurodegeneration; Neurotrophic functions; Opsins - genetics; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Pathogenesis; Photoreceptors; Physiological aspects; Receptors, LDL - genetics; Retina; Retina - abnormalities; Retina - drug effects; Retina - metabolism; Retina - pathology; Retina - physiopathology; Retinal Cone Photoreceptor Cells - drug effects; Retinal Cone Photoreceptor Cells - pathology; Retinal Cone Photoreceptor Cells - physiology; Retinal Neovascularization - complications; Retinal Neovascularization - genetics; Retinal Neovascularization - pathology; Retinal Neovascularization - physiopathology; Retinal Neovascularization - prevention & control; Retinal Pigment Epithelium - abnormalities; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Retinal Rod Photoreceptor Cells - drug effects; Retinal Rod Photoreceptor Cells - pathology; Retinal Rod Photoreceptor Cells - physiology; Retinitis Pigmentosa - etiology; Retinitis Pigmentosa - metabolism; Retinitis Pigmentosa - pathology; Retinitis Pigmentosa - prevention & control; Rhodopsin - genetics; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - genetics
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci35977

In several disease states, abnormal growth of blood vessels is associated with local neuronal degeneration. This is particularly true in ocular diseases such as retinal angiomatous proliferation (RAP) and macular telangiectasia (MacTel), in which, despite the absence of large-scale leakage or hemorrhage, abnormal neovascularization (NV) is associated with local neuronal dysfunction. We describe here a retinal phenotype in mice with dysfunctional receptors for VLDL (Vldlr-/- mice) that closely resembles human retinal diseases in which abnormal intra- and subretinal NV is associated with photoreceptor cell death. Such cell death was evidenced by decreased cone and, to a lesser extent, rod opsin expression and abnormal electroretinograms. Cell death in the region of intraretinal vascular abnormalities was associated with an increased presence of markers associated with oxidative stress. Oral antioxidant supplementation protected against photoreceptor degeneration and preserved retinal function, despite the continued presence of abnormal intra- and subretinal vessels. What we believe to be novel, Müller cell-based, virally mediated delivery of neurotrophic compounds specifically to sites of NV was also neuroprotective. These observations demonstrate that neuronal loss secondary to NV can be prevented by the use of simple antioxidant dietary measures or cell-based delivery of neurotrophic factors, even when the underlying vascular phenotype is not altered.