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J Am Coll Cardiol, 2004; 44:661-666, doi:10.1016/j.jacc.2004.04.046 © 2004 by the American College of Cardiology Foundation |

* Third Department of Internal Medicine and Cardiovascular Research Institute, Kurume University, Kurume, Japan
Cardiovascular Medicine, Kyushu University Graduate School of Medicine, Fukuoka, Japan
Manuscript received January 7, 2004; revised manuscript received March 18, 2004, accepted April 20, 2004.
* Reprint requests and correspondence: Dr. Hisashi Kai, Third Department of Internal Medicine and Cardiovascular Research Institute, Kurume University, 67 Asahi-machi, Kurume 830-0011, Japan (Email: naikai{at}med.kurume-u.ac.jp).
OBJECTIVES: We sought to investigate the role of endogenous monocyte chemoattractant protein (MCP)-1 in ischemia-induced neovascularization.
BACKGROUND: Roles of inflammatory changes including macrophage infiltration are suggested in ischemic neovascularization.
METHODS: Unilateral hindlimb ischemia was induced by excising surgically the entire femoral artery and vein in mice. Immediately after operation, plasmid deoxyribonucleic acid encoding a dominant negative mutant of MCP-1 (7ND) or the empty plasmid (mock) was injected into the ipsilateral thigh adductor muscle.
RESULTS: In mock-treated mice, MCP-1 was upregulated transiently in ischemic hindlimb peaking at day 3. Serial laser Doppler blood flow (LDBF) analysis showed an abrupt decrease in blood flow, followed by a recovery to the near-normal levels in mock-treated mice; 7ND treatment had no effects on the initial decrease in LDBF but deteriorated the recovery. At day 3, macrophage infiltration and inductions of tumor necrosis factor (TNF)-alpha and vascular endothelial growth factor (VEGF) were prominent in the ischemic adductor muscle in mock-treated mice; 7ND treatment significantly reduced macrophage infiltration and suppressed TNF-alpha and VEGF inductions in response to ischemia. At day 21, postmortem angiography and anti-CD31 immunohistostaining revealed well-developed collateral vessels and capillary formation, respectively, in the ischemic muscle of mock-treated mice; 7ND overexpression remarkably suppressed the collateral vessel formation and capillary formation.
CONCLUSIONS: Endogenous MCP-1 may play a role in ischemia-induced neovascularization by recruiting macrophages that activate TNF-alpha and VEGF inductions.
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