Fujii Takaaki, Yonemitsu Yoshikazu, Onimaru Mitsuho, Tanii Mitsugu, Nakano Toshiaki, Egashira Kensuke, Takehara Takako, Inoue Makoto, Hasegawa Mamoru, Kuwano Hiroyuki, Sueishi Katsuo
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.
Arterioscler Thromb Vasc Biol. 2006 Nov;26(11):2483-9. doi: 10.1161/01.ATV.0000244684.23499.bf. Epub 2006 Sep 7.
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.
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.
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.
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。血管生成参与炎症过程；然而，炎症途径、动脉生成和血管生成之间联系的分子和细胞机制尚未完全阐明。
利用成纤维细胞生长因子-2（FGF-2）介导的治疗性新生血管形成的小鼠模型，我们在此表明FGF-2作用于非内皮间充质细胞（NEMC），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表达，FGF-2基因转移可使其强烈增强，通过显性负突变体阻断MCP-1活性以及其功能性受体CCR2缺乏会导致适应性和治疗性新生血管形成引起的血流恢复减少。肿瘤坏死因子（TNF）-α刺激所有测试细胞类型中的MCP-1表达，而FGF-2介导的MCP-1上调仅在NEMC中发现，在其他细胞中未发现，这一发现不受体外和体内VEGF的影响。
这些结果表明FGF-2独立作用于NEMC，增强血管生成（VEGF）以及炎症/动脉生成（MCP-1）途径。因此，MCP-1/CCR2在适应性和FGF-2介导的治疗性新生血管形成中起关键作用。
