Nonendothelial mesenchymal cell-derived MCP-1 is required for FGF-2-mediated therapeutic neovascularization - Critical role of the inflammatory/arteriogenic pathway
Nonendothelial mesenchymal cell-derived MCP-1 is required for FGF-2-mediated therapeutic neovascularization - Critical role of the inflammatory/arteriogenic pathway
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DOI：
10.1161/01.atv.0000244684.23499.bf
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发表时间：
2006-11-01
影响因子：
8.7
通讯作者：
Sueishi, Katsuo
中科院分区：
文献类型：
--
作者：
Fujii, Takaaki;Yonemitsu, Yoshikazu;Sueishi, Katsuo
目的-单核细胞趋化蛋白-1（MCP- 1）是一种C-C趋化因子，被认为是一种炎症/动脉生成因子。血管生成促进炎症过程;方法和结果-使用成纤维细胞生长因子-2（FGF- 2）介导的治疗性新血管形成的鼠模型，我们发现FGF- 2靶向非内皮间充质细胞（NEMCs），通过独立的信号转导途径增强血管生成（血管内皮生长因子[ VEGF]）和动脉生成（MCP- 1）信号。严重的后肢缺血刺激MCP- 1的表达，强烈增强FGF- 2基因转移，和MCP- 1活性的阻断通过显性负突变体以及其功能性受体CCR 2的缺陷导致血流的恢复减少归因于适应性和治疗性新血管形成。肿瘤坏死因子（TNF）-α在所有测试的细胞类型中刺激MCP- 1表达，而FGF- 2介导的MCP- 1上调仅在NEMC中发现，而在其他细胞中未发现，这一发现在体外和体内均不受VEGF影响。增强血管生成（VEGF）以及炎症/动脉生成（MCP- 1）途径。因此，MCP-1/CCR 2在适应性和FGF- 2介导的治疗性新血管形成中起关键作用。
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.