Nonendothelial Mesenchymal Cell–Derived MCP-1 Is Required for FGF-2–Mediated Therapeutic Neovascularization: Critical Role of the Inflammatory/Arteriogenic Pathway

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 26; no. 11; pp. 2483 - 2489
• Main Authors: Fujii, Takaaki, Yonemitsu, Yoshikazu, Onimaru, Mitsuho, Tanii, Mitsugu, Nakano, Toshiaki, Egashira, Kensuke, Takehara, Takako, Inoue, Makoto, Hasegawa, Mamoru, Kuwano, Hiroyuki, Sueishi, Katsuo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.11.2006; Hagerstown, MD Lippincott
• Subjects: Adaptation, Physiological; Animals; Arteries - growth & development; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cardiovascular system; Chemokine CCL2 - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Fundamental and applied biological sciences. Psychology; Gene Transfer Techniques; Hindlimb - blood supply; Inflammation Mediators - metabolism; Ischemia - metabolism; Ischemia - physiopathology; Male; Medical sciences; Mesoderm - cytology; Mesoderm - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases - metabolism; Neovascularization, Physiologic; NF-kappa B - metabolism; Pharmacology. Drug treatments; Protein Kinase C - metabolism; Receptors, CCR2; Receptors, Chemokine - metabolism; Regional Blood Flow; Signal Transduction; Vascular Endothelial Growth Factor A - metabolism; Vasodilator agents. Cerebral vasodilators; Vertebrates: cardiovascular system; Vascular disease; FGF-2; MCP-1; Treatment; angiogenesis; Atherosclerosis; Cardiovascular disease; Neovascularization; mesenchymal cells; arteriogenesis
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000244684.23499.bf

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.