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O steopontin (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.