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Osteopontin (OPN) is expressed in atherosclerotic lesions, particularly in diabetic patients. To determine the role of OPN in atherogenesis, ApoE−/−OPN+/+, ApoE−/−OPN+/−, and ApoE−/−OPN−/− mice were infused with Ang II, inducing vascular OPN expression and accelerating atherosclerosis. Compared with ApoE−/−OPN+/+ mice, ApoE−/−OPN+/− and ApoE−/−OPN−/− mice developed less Ang II-accelerated atherosclerosis. ApoE−/− mice transplanted with bone marrow derived from ApoE−/−OPN−/− mice had less Ang II-induced atherosclerosis compared with animals receiving ApoE−/−OPN+/+ cells. Aortae from Ang II-infused ApoE−/−OPN−/− mice expressed less CD68, C-C-chemokine receptor 2, and VCAM-1. In response to intraperitoneal thioglycollate, recruitment of leukocytes in OPN−/− mice was impaired, and OPN−/− leukocytes exhibited decreased basal and MCP-1-directed migration. Furthermore, macrophage viability in atherosclerotic lesions from Ang II-infused ApoE−/−OPN−/− mice was decreased. Finally, Ang II-induced abdominal aortic aneurysm formation in ApoE−/−OPN−/− mice was reduced and associated with decreased MMP-2 and MMP-9 activity. These data suggest an important role for leukocyte-derived OPN in mediating Ang II-accelerated atherosclerosis and aneurysm formation.