CCR2 -/- knockout mice revascularize normally in response to severe hindlimb ischemia

Abstract

Monocyte chemoattractant protein-1 (MCP-1) is reported to stimulate ischemia-induced arteriogenesis (collateral artery development) by recruiting monocytes and macrophages into areas of active arteriogenesis. To determine whether the MCP-1-mediated response occurs through its receptor, CC-chemokine receptor 2 (CCR2), we induced hindlimb ischemia in mice lacking the receptor for MCP-1 (CCR2 -/- ) and measured limb blood flow recovery, collateral artery development, and monocyte and macrophage recruitment. Hindlimb ischemia was induced by excising the left femoral artery in CCR2 -/- and wild-type mice. Hindlimb blood flow recovery, as measured using laser Doppler perfusion imaging, was equivalent in both groups ( P = .78 for foot and P = 0.38 for calf). Collateral artery development, as measured by angiography at postoperative day 14 and 31, likewise did not differ between the 2 groups ( P = .46 and P = .67). Counts of monocytes and macrophages in calf and thigh muscle sections of mice sacrificed on postoperative day 7 revealed that although CCR2 -/- mice recruited 44% fewer monocytes and macrophages to areas of ischemia in the calf, they recruited similar numbers of monocytes and macrophages to areas of active arteriogenesis in the thigh. Intercellular adhesion molecule-1 and MCP-1 mRNA levels were higher in the thigh muscle of CCR2 -/- mice than in wild-type mice (5.5-fold and 42.3-fold induction operated to unoperated vs 2.6-fold and 6.1-fold induction operated to unoperated, respectively). Blood flow recovery, arteriogenesis, and monocyte and macrophage recruitment to the thigh was normal in CCR2 -/- mice. However, monocyte and macrophage recruitment to the ischemic calf was diminished in CCR2 -/- mice. Our results show that MCP-1 signaling through CCR2 is not required for physiologic arteriogenesis in response to severe hindlimb ischemia. ICAM-1 upregulation may substitute for MCP-1 signaling through CCR2 in order to allow normal arteriogenesis in CCR2 -/- mice.