Nonendothelial mesenchymal cell-derived MCP-1 is required for FGF-2-mediated therapeutic neovascularization: Critical role of the inflammatory/arteriogenic pathway

Takaaki Fujii, Yoshikazu Yonemitsu, Mitsuho Onimaru, Mitsugu Tanii, Toshiaki Nakano, Kensuke Egashira, Takako Takehara, Makoto Inoue, Mamoru Hasegawa, Hiroyuki Kuwano, Katsuo Sueishi

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Abstract

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. METHODS AND 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)-α 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.

Original languageEnglish
Pages (from-to)2483-2489
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume26
Issue number11
DOIs
Publication statusPublished - Nov 1 2006

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All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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