title: Antioxidant or neurotrophic factor treatment preserves function in a mouse model of neovascularization-associated oxidative stress.
abstract: 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.
authors.affiliation: Department of Cell Biology, Scripps Center for Mass Spectrometry, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Dorrell
authors.forename: Edith
authors.initials: E
authors.lastname: Aguilar
authors.forename: Ruth
authors.initials: R
authors.lastname: Jacobson
authors.forename: Oscar
authors.initials: O
authors.lastname: Yanes
authors.forename: Ray
authors.initials: R
authors.lastname: Gariano
authors.forename: John
authors.initials: J
authors.lastname: Heckenlively
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: G Anthony
authors.initials: GA
authors.lastname: Ramirez
authors.forename: Mehdi
authors.initials: M
authors.lastname: Gasmi
authors.forename: Alan
authors.initials: A
authors.lastname: Bird
authors.forename: Gary
authors.initials: G
authors.lastname: Siuzdak
authors.forename: Martin
authors.initials: M
authors.lastname: Friedlander
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000627:therapeutic use; D004195:Disease Models, Animal; D004596:Electroretinography; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D015227:Lipid Peroxidation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D055355:Opsins / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011973:Receptors, LDL / Q000235:genetics; D012160:Retina / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D015861:Retinal Neovascularization / Q000150:complications* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D055213:Retinal Pigment Epithelium / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D012174:Retinitis Pigmentosa / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012243:Rhodopsin / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D000975:Antioxidants; D052157:Aptamers, Nucleotide; D009414:Nerve Growth Factors; D055355:Opsins; D011973:Receptors, LDL; C036053:VLDL receptor; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C495058:pegaptanib; D012243:Rhodopsin; C073922:neurotrophin 4