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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:283.)
© 2007 American Heart Association, Inc.

Vascular Biology

M-CSF Accelerates Neointimal Formation in the Early Phase After Vascular Injury in Mice

The Critical Role of the SDF-1–CXCR4 System

Yuji Shiba; Masafumi Takahashi; Toru Yoshioka; Noriyuki Yajima; Hajime Morimoto; Atsushi Izawa; Hirohiko Ise; Kiyohiko Hatake; Kazuo Motoyoshi; Uichi Ikeda

From the Division of Cardiovascular Sciences, Department of Organ Regeneration (Y.S., M.T., T.Y., N.Y., H.M., A.I., H.I., U.I.), Shinshu University Graduate School of Medicine, Matsumoto; the Cancer Chemotherapy Center (K.H.), Japanese Foundation for Cancer Research, Tokyo; and the Third Department of Internal Medicine (K.M.), National Defense Medical College, Saitama, Japan.

Correspondence to Masafumi Takahashi, MD, PhD, Division of Cardiovascular Sciences, Department of Organ Regeneration, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. E-mail masafumi{at}sch.md.shinshu-u.ac.jp

Objective— Since the macrophage colony-stimulating factor (M-CSF) has been shown to stimulate differentiation and proliferation of monocyte/macrophage lineage and to be involved in the process of neointimal formation after vascular injury, we tested the effects of M-CSF on the recruitment of bone marrow-derived progenitor cells in neointimal formation after vascular injury in mice.

Methods and Results— Wire-mediated vascular injury was produced in the femoral artery of C57BL/6 mice. Recombinant human M-CSF [500 µg/(kg·day)] or saline (control) was administered for 10 consecutive days, starting 4 days before the injury. Treatment with M-CSF accelerated neointimal formation in the early phase after injury, and this neointimal lesion mainly consisted of bone marrow-derived cells. M-CSF treatment had no effect on the mobilization of endothelial progenitor cells (EPCs: CD34⁺/Flk-1⁺) and reendothelialization after injury. The stromal cell-derived factor-1 (SDF-1) was markedly expressed in the neointima and media after injury, whereas CXCR4⁺ cells were observed in the neointima. Further, a novel CXCR4 antagonist, AMD3100, significantly attenuated the M-CSF-induced neointimal formation.

Conclusions— These findings suggest that M-CSF accelerated neointimal formation after vascular injury via the SDF-1–CXCR4 system, and the inhibition of this system has therapeutic potential for the treatment of cardiovascular diseases.

We tested the effects of M-CSF on the recruitment of bone marrow-derived progenitor cells in neointimal formation after vascular injury in mice. The findings obtained from this study demonstrated that M-CSF accelerated neointimal formation in the early phase after vascular injury via the SDF-1–CXCR4 system.

Key Words: angioplasty • cytokines • inflammation • restenosis • vascular biology

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CXCR4, a Key Modulator of Vascular Progenitor Cells

Julie Sainz and Masataka Sata
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