TY - JOUR
T1 - Vascular cell-adhesion molecule-1 plays a central role in the proangiogenic effects of oxidative stress
AU - Dong, Aling
AU - Shen, Jikui
AU - Zeng, Ming Bing
AU - Campochiaro, Peter A.
PY - 2011/8/30
Y1 - 2011/8/30
N2 - 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.
AB - 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.
KW - Age-related macular degeneration
KW - Diabetic retinopathy
KW - Reactive oxygen species
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U2 - 10.1073/pnas.1012859108
DO - 10.1073/pnas.1012859108
M3 - Article
C2 - 21844360
AN - SCOPUS:80052278961
SN - 0027-8424
VL - 108
SP - 14614
EP - 14619
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 35
ER -