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: Aling Dong, Jikui Shen, MingBing Zeng, Peter A Campochiaro
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 35 Pg. 14614-9 (Aug 30 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21844360 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Hypoxia-Inducible Factor 1
• NF-kappa B
• Vascular Cell Adhesion Molecule-1
• Sod1 protein, mouse
• Superoxide Dismutase
• Superoxide Dismutase-1

Topics

• Animals
• Hypoxia-Inducible Factor 1 (physiology)
• Ischemia (metabolism)
• Leukostasis (etiology)
• Mice
• NF-kappa B (physiology)
• Oxidative Stress
• Retinal Neovascularization (etiology)
• Superoxide Dismutase (physiology)
• Superoxide Dismutase-1
• Vascular Cell Adhesion Molecule-1 (physiology)