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Roles of endogenous monocyte chemoattractant protein-1 in ischemia-induced neovascularization

Hiroshi Niiyama, MD^*, Hisashi Kai, MD, PhD^*,*, Tomoka Yamamoto, BS^*, Toshifumi Shimada, MD^*, Ken-Ichiro Sasaki, MD, PhD^*, Toyoaki Murohara, MD, PhD^*, Kensuke Egashira, MD, PhD and Tsutomu Imaizumi, MD, PhD, FACC^*

^* 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.

Abbreviations and Acronyms   DNA = deoxyribonucleic acid   EC = endothelial cell   LDBF = laser Doppler blood flow   MCP-1 = monocyte chemoattractant protein-1   TNF = tumor necrosis factor   VEGF = vascular endothelial growth factor   7ND = a dominant negative mutant of MCP-1 lacking the N-terminal amino acids 2 to 8

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