Roles of endogenous monocyte chemoattractant protein-1 in ischemia-induced neovascularization.
OBJECTIVE
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.
Niiyama
Hiroshi
H
Third Department of Internal Medicine and Cardiovascular Research Institute, Kurume University, Kurume, Japan.
Kai
Hisashi
H
Yamamoto
Tomoka
T
Shimada
Toshifumi
T
Sasaki
Ken-Ichiro
K
Murohara
Toyoaki
T
Egashira
Kensuke
K
Imaizumi
Tsutomu
T
D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism*; D006614:Hindlimb; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology*; D017078:Laser-Doppler Flowmetry; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000737:chemistry / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A