title: Vascular cell-adhesion molecule-1 plays a central role in the proangiogenic effects of oxidative stress.
abstract: Oxidative stress exacerbates neovascularization (NV) in many disease processes. In this study we investigated the mechanism of that effect. Mice deficient in superoxide dismutase 1 (Sod1(-/-) mice) have increased oxidative stress and show severe ocular NV that is reduced to baseline by antioxidants. Compared with wild-type mice with ischemic retinopathy, Sod1(-/-) mice with ischemic retinopathy had increased expression of several NF-κB-responsive genes, but expression of vascular cell-adhesion molecule-1 (Vcam1) was particularly high. Intraocular injection of anti-VCAM-1 antibody eliminated the excessive ischemia-induced retinal NV. Elements that contributed to oxidative stress-induced worsening of retinal NV that were abrogated by blockade of VCAM-1 included increases in leukostasis, influx of bone marrow-derived cells, and capillary closure. Compared with ischemia alone, ischemia plus oxidative stress resulted in increased expression of several HIF-1-responsive genes caused in part by VCAM-1-induced worsening of nonperfusion and, hence, ischemia, because anti-VCAM-1 significantly reduced the increased expression of all but one of the genes. These data explain why oxidative stress worsens ischemia-induced retinal NV and may be relevant to other neovascular diseases in which oxidative stress has been implicated. The data also suggest that antagonism of VCAM-1 provides a potential therapy to combat worsening of neovascular diseases by oxidative stress.
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-9277, USA.
authors.forename: Aling
authors.initials: A
authors.lastname: Dong
authors.forename: Jikui
authors.initials: J
authors.lastname: Shen
authors.forename: MingBing
authors.initials: M
authors.lastname: Zeng
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D000818:Animals; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology; D007511:Ischemia / Q000378:metabolism; D018921:Leukostasis / Q000209:etiology; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress; D015861:Retinal Neovascularization / Q000209:etiology*; D013482:Superoxide Dismutase / Q000502:physiology; D000072105:Superoxide Dismutase-1; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1