Circulation Research. 2002
Published online before print December 19, 2002, doi: 10.1161/01.RES.0000052313.23087.3F
Published online before print December 19, 2002, doi: 10.1161/01.RES.0000052313.23087.3F
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Submitted on July 26, 2002
Revised on November 27, 2002
Accepted on December 4, 2002
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
N. van Royen *;
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.
* To whom correspondence should be addressed. E-mail: n.vanroyen{at}amc.uva.nl.
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<0.0001). 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.
Key words: arteriogenesis • collateral circulation • atherosclerosis • monocytes • monocyte chemoattractant protein-1
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