Open AccessVascular cell-adhesion molecule-1 plays a central role in the proangiogenic effects of oxidative stress
Author(s) -
Aling Dong,
Jikui Shen,
Ming Bing Zeng,
Peter A. Campochiaro
Publication year - 2011
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1012859108
Subject(s) - oxidative stress , ischemia , sod1 , cell adhesion molecule , superoxide dismutase , vcam 1 , neovascularization , pharmacology , medicine , endocrinology , immunology , angiogenesis , icam 1
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 ofvascular 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.