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.
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.
van Royen
N
N
Department of Cardiology, University of Amsterdam, Amsterdam, The Netherlands. n.vanroyen@amc.uva.nl
Hoefer
I
I
Böttinger
M
M
Hua
J
J
Grundmann
S
S
Voskuil
M
M
Bode
C
C
Schaper
W
W
Buschmann
I
I
Piek
J J
JJ
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001158:Arteries / Q000187:drug effects* / Q000473:pathology; D001161:Arteriosclerosis / Q000473:pathology; D039481:CD11b Antigen / Q000096:biosynthesis*; D018932:Chemokine CCL2 / Q000009:adverse effects / Q000494:pharmacology*; D003097:Collateral Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012039:Regional Blood Flow / Q000187:drug effects; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D001057:Apolipoproteins E; D039481:CD11b Antigen; D018932:Chemokine CCL2; D008055:Lipids