Neutralizing Antibodies Directed Against Osteopontin Inhibit Rat Carotid Neointimal Thickening After Endothelial Denudation

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Abstract
Osteopontin is an arginine-glycine-aspartate-containing acidic glycoprotein with adhesive and migratory activities in vitro. We previously showed that osteopontin was highly expressed in injured rat arteries as well as in human atherosclerotic plaques. In contrast, uninjured blood vessels make very little osteopontin. In this report, we have investigated the role of osteopontin in rat neointima formation using neutralizing antibodies. Rats were treated with either nonimmune or antiosteopontin antibody and subjected to endothelial denudation of the carotid artery by using a balloon catheter. Two weeks after injury, intimal areas and cell numbers were significantly decreased (33% and 31%, respectively) in the antiosteopontin group compared with the nonimmune IgG group. No differences in carotid medial areas or cell numbers were observed. Intimal and medial replication rates, as measured by continuous bromodeoxyuridine infusion during the final week of the experimental protocol, were not significantly different between the two groups. No gross histological changes were noted in the intimas formed in the presence of either neutralizing or nonimmune antibody. In addition, no difference in early carotid medial cell replication rate was observed when antibodies were infused for 4 days after angioplasty. These data demonstrate for the first time a functional role for osteopontin in the process of carotid neointimal thickening in vivo and suggest that osteopontin plays an active role in the remodeling processes important for human atherosclerotic and restenotic lesion development.