Nonendothelial mesenchymal cell-derived MCP-1 is required for FGF-2-mediated therapeutic neovascularization: critical role of the inflammatory/arteriogenic pathway.
OBJECTIVE
Monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine that is known as an inflammatory/arteriogenic factor. Angiogenesis contributes to the inflammatory process; however, the molecular and cellular mechanisms of the links among the inflammatory pathway, arteriogenesis, and angiogenesis have not been well elucidated.


RESULTS
Using murine models of fibroblast growth factor-2 (FGF-2)-mediated therapeutic neovascularization, we here show that FGF-2 targets nonendothelial mesenchymal cells (NEMCs) enhancing both angiogenic (vascular endothelial growth factor [VEGF]) and arteriogenic (MCP-1) signals via independent signal transduction pathways. Severe hindlimb ischemia stimulated MCP-1 expression that was strongly enhanced by FGF-2 gene transfer, and a blockade of MCP-1 activity via a dominant negative mutant as well as a deficiency of its functional receptor CCR2 resulted in the diminished recovery of blood flow attributable to adaptive and therapeutic neovascularization. Tumor necrosis factor (TNF)-alpha stimulated MCP-1 expression in all cell types tested, whereas FGF-2-mediated upregulation of MCP-1 was found only in NEMCs but not in others, a finding that was not affected by VEGF in vitro and in vivo.


CONCLUSIONS
These results indicate that FGF-2 targets NEMCs independently, enhancing both angiogenic (VEGF) as well as inflammatory/arteriogenic (MCP-1) pathways. Therefore, MCP-1/CCR2 plays a critical role in adaptive and FGF-2-mediated therapeutic neovascularization.
Fujii
Takaaki
T
Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Yonemitsu
Yoshikazu
Y
Onimaru
Mitsuho
M
Tanii
Mitsugu
M
Nakano
Toshiaki
T
Egashira
Kensuke
K
Takehara
Takako
T
Inoue
Makoto
M
Hasegawa
Mamoru
M
Kuwano
Hiroyuki
H
Sueishi
Katsuo
K
D000222:Adaptation, Physiological; D000818:Animals; D001158:Arteries / Q000254:growth & development; D018932:Chemokine CCL2 / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D018014:Gene Transfer Techniques; D006614:Hindlimb / Q000098:blood supply; D018836:Inflammation Mediators / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic; D011493:Protein Kinase C / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000378:metabolism; D012039:Regional Blood Flow; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D016328:NF-kappa B; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases