Abnormal monocyte recruitment and collateral artery formation in monocyte chemoattractant protein-1 deficient mice

Abstract

Monocyte chemoattractant protein 1 (MCP-1) has been shown to be effective for the stimulation of collateral artery formation in small and large animal models. The availability of a genetic knockout mouse enables evaluation of the importance of the role of MCP-1 in the natural course of collateral artery growth. In a total of 21 MCP-1 = as well as 13 of the appropriate genetic background controls (f129Sv=JXC57Bl=6JgF1), a femoral artery ligation was performed. Subsequently, a polyethylene catheter, connected to an osmotic minipump, was inserted retrogradely into the occluded femoral artery with the tip pointing upstream. Using this technique, PBS (MCP-1 =: n ¹/4-13 and C57Bl=6J: n ¹/4-13) or MCP-1 (JE; MCP-1 =: n ¹/4-8) was delivered intra-arterially. Seven days after ligation, determination of hind limb flow was assessed by controlled tissue perfusion using differently labeled fluorescent microspheres. MCP-1 = mice exhibited a reduction of hind limb flow of 32.9-9.2% of the unligated hind limb, compared with 55.4-6.8% in C57Bl=6J mice (p <0.01). MCP-1= mice that underwent a subsequent ‘rescue’ treatment with MCP-1 showed a restoration of flow to a level of 47.4-9.8% (p ¹/4 NS compared with PBS-treated C57Bl/6J). Specific immunohistochemical staining for monocytes (MOMA-2: MCP-1 =, n ¹/4-5 and C57Bl/6J, n ¹/4-5) showed a reduced number of monocytes around developing collateral arteries in the MCP-1 = mice. In conclusion, our data show that the absence of MCP-1 causes a strong reduction in flow restoration after femoral artery occlusion, coinciding with a reduced monocyte attraction, emphasizing the central role of this chemokine in the multifactorial process of collateral artery formation.

Keywords

collateral circulation cytokines macrophages regional blood flow

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