The Role of Osteopontin in Recovery from Hind Limb Ischemia

Objective—Osteopontin (OPN) is a highly phosphorylated extracellular matrix glycoprotein that is involved in a diversity of biological processes. In the vascular wall, OPN is produced by monocytes/macrophages, endothelial cells, and smooth muscle cells, and it is thought to mediate adhesion, migration, and survival of these cell types. In this study, we hypothesized that OPN plays a critical role in recovery from limb ischemia. Methods and Results—We induced hind limb ischemia in wild-type and OPN−/− mice. OPN−/− mice exhibited significantly delayed recovery of ischemic foot perfusion as determined by LDPI, impaired collateral vessel formation as measured using micro-CT, and diminished functional capacity of the ischemic limb. In the aortic ring assay, normal endothelial cell sprouting was found in OPN−/− mice. However, OPN−/− peritoneal monocytes/macrophages were found to possess significantly reduced migration in response to chemoattraction. Conclusions—This study provides evidence that a definitive biological role exists for OPN during ischemic limb revascularization, and we have suggested that this may be driven by impaired monocyte/macrophage migration in OPN−/− mice. These findings provide the first in vivo evidence that OPN may be a key regulator in postnatal vascular growth.