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.

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 microg/kg per week), high-dose MCP-1 (10 microg/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.

• Authors: N van Royen, I Hoefer, M Böttinger, J Hua, S Grundmann, M Voskuil, C Bode, W Schaper, I Buschmann, J J Piek
• Journal: Circulation research (Circ Res) Vol. 92 Issue 2 Pg. 218-25 (Feb 07 2003) ISSN: 1524-4571 [Electronic] United States
• PMID: 12574150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• CD11b Antigen
• Chemokine CCL2
• Lipids

Topics

• Animals
• Apolipoproteins E (deficiency, genetics)
• Arteries (drug effects, pathology)
• Arteriosclerosis (pathology)
• CD11b Antigen (biosynthesis)
• Chemokine CCL2 (adverse effects, pharmacology)
• Collateral Circulation (drug effects)
• Disease Models, Animal
• Disease Progression
• Dose-Response Relationship, Drug
• Femoral Artery (drug effects, pathology)
• Flow Cytometry
• Immunohistochemistry
• Lipids (blood)
• Macrophages (drug effects, pathology)
• Mice
• Mice, Knockout
• Monocytes (drug effects, metabolism, pathology)
• Regional Blood Flow (drug effects)
• Tunica Intima (drug effects, pathology)