M-CSF accelerates neointimal formation in the early phase after vascular injury in mice the critical role of the SDF-1-CXCR4 system

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 mu g/( 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.