Local Monocyte Chemoattractant Protein-1 Therapy Increases Collateral Artery Formation in Apolipoprotein E–Deficient Mice but Induces Systemic Monocytic CD11b Expression, Neointimal Formation, and Plaque Progression

Author:

van Royen N.1,Hoefer I.1,Böttinger M.1,Hua J.1,Grundmann S.1,Voskuil M.1,Bode C.1,Schaper W.1,Buschmann I.1,Piek J.J.1

Affiliation:

1. From the Department of Cardiology (N.v.R., M.V., J.J.P.), University of Amsterdam, Amsterdam, the Netherlands; the Department of Cardiology (N.v.R., I.H., M.B., J.H., S.G., C.B., I.B.), University of Freiburg, Freiburg, Germany; and the Department of Experimental Cardiology (W.S.), Max Planck Institute, Bad Nauheim, Germany.

Abstract

Monocyte chemoattractant protein-1 (MCP-1) stimulates the formation of a collateral circulation on arterial occlusion. The present study served to determine whether these proarteriogenic properties of MCP-1 are preserved in hyperlipidemic apolipoprotein E–deficient (apoE −/− ) mice and whether it affects the systemic development of atherosclerosis. A total of 78 apoE −/− mice were treated with local infusion of low-dose MCP-1 (1 μg/kg per week), high-dose MCP-1 (10 μg/kg per week), or PBS as a control after unilateral ligation of the femoral artery. Collateral hindlimb flow, measured with fluorescent microspheres, significantly increased on a 1-week high-dose MCP-1 treatment (PBS 22.6±7.2%, MCP-1 31.3±10.3%; P <0.05). These effects were still present 2 months after the treatment (PBS 44.3±4.6%, MCP-1 56.5±10.4%; P <0.001). The increase in collateral flow was accompanied by an increase in the number of perivascular monocytes/macrophages on MCP-1 treatment. However, systemic CD11b expression by monocytes also increased, as did monocyte adhesion at the aortic endothelium and neointimal formation (intima/media ratio, 0.097±0.011 [PBS] versus 0.257±0.022 [MCP-1]; P <0.0001). Moreover, Sudan IV staining revealed an increase in aortic atherosclerotic plaque surface (24.3±5.2% [PBS] versus 38.2±9.5% [MCP-1]; P <0.01). Finally, a significant decrease in the percentage of smooth muscle cells was found in plaques (15.0±5.2% [PBS] versus 5.8±2.3% [MCP-1]; P <0.001). In conclusion, local infusion of MCP-1 significantly increases collateral flow on femoral artery ligation in apoE −/− mice up to 2 months after the treatment. However, the local treatment did not preclude systemic effects on atherogenesis, leading to increased atherosclerotic plaque formation and changes in cellular content of plaques.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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