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

被引:54
作者
Fujii, Takaaki
Yonemitsu, Yoshikazu
Onimaru, Mitsuho
Tanii, Mitsugu
Nakano, Toshiaki
Egashira, Kensuke
Takehara, Takako
Inoue, Makoto
Hasegawa, Mamoru
Kuwano, Hiroyuki
Sueishi, Katsuo
机构
[1] Kyushu Univ, Grad Sch Med Sci, Dept Cardiovasc Med, Fukuoka 8128582, Japan
[2] Gunma Univ, Dept Gen Surg Sci, Grad Sch Med, Gunma, Japan
[3] DNAVEC Corp, Tsukuba, Ibaraki, Japan
[4] Kyushu Univ, Div Pathophysiol & Expt Pathol, Dept Pathol, Grad Sch Med Sci,Higashi Ku, Fukuoka 8128582, Japan
关键词
MCP-1; FGF-2; arteriogenesis; angiogenesis; mesenchymal cells;
D O I
10.1161/01.ATV.0000244684.23499.bf
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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)-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.
引用
收藏
页码:2483 / 2489
页数:7
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