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on September 7, 2006

Arteriosclerosis, Thrombosis, and Vascular Biology. 2006
Published online before print September 7, 2006, doi: 10.1161/01.ATV.0000244684.23499.bf
A more recent version of this article appeared on November 1, 2006
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Submitted on March 3, 2006
Accepted on August 20, 2006

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 ; and Katsuo Sueishi

From the Division of Pathophysiological and Experimental Pathology, Departments of Pathology (T.F., Y.Y., M.O., T.N., T.T., K.S.) and Cardiovascular Medicine (K.E.), Graduate School of Medical Science, Kyushu University, Fukuoka; the Department of General Surgical Science (T.F., H.K.), Graduate School of Medicine, Gunma University, Gunma; and DNAVEC Corporation (M.I., M.H.), Tsukuba, Ibaraki, Japan. Present address for ••: Department of Gene Therapy at the 21Century Center of Excellence Program, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

* To whom correspondence should be addressed. E-mail: yonemitu{at}med.kyushu-u.ac.jp.

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.
Key words: MCP-1 • FGF-2 • arteriogenesis • angiogenesis • mesenchymal cells




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