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


RESULTS
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).


CONCLUSIONS
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.
Tang
Gale
G
Pacific Vascular Research Laboratory, Department of Surgery, Division of Vascular Surgery, University of California, San Francisco 94143-0222, USA.
Charo
David N
DN
Wang
Rong
R
Charo
Israel F
IF
Messina
Louis
L
D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology; D018932:Chemokine CCL2 / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology; D005260:Female; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000503:physiopathology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009000:Monocytes / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000502:physiology*
C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine