BACKGROUND : Angiogenesis is implicated in the growth of atheromatous plaque. Together with other chemokines such as MCP-1 and SDF-1, a novel chemokine CX3CL1 (fractalkine; FKN) is expressed in the atherosclerotic lesion and reportedly plays significant roles on the vascular trafficking of monocytes and T cells. In this study we investigated if FKN induces angiogenesis using in vivo (i.e. measuring capillary growth in chick chorioallantoic membranes (CAM); CAM assay) and ex vivo (i.e. the tube formation from the excised rat aortic ring cultured on Matrigel; rat aortic ring assay) experimental models. RESULTS : The result of CAM assay and rat aortic ring assay showed that recombinant human FKN induced the vessel formation in a dose dependent manner (20-200ng/ml). The culture of excised rat aortic rings with FKN increased the mRNA amount of VEGF (VEGF-A) and VEGF cytokine family, VEGF-C and VEGF-D. Accordingly, the CAM assay showed that the FKN-induced angiogenesis was completely suppressed by VEGF-inhibitor. A Rho protein inhibitor, Clostridium difficile toxine B, and a specific RhoA inhibitor C3 transferase also inhibited the FKN-induced angiogenesis. Pretreatment of excised rat aortic rings and CAM with HMG-CoA reductase inhibitor, simvastatin, completely blocked the angiogeneic property of FKN and decreased mRNA amounts of VEGF-A, -C and -D, while a PPARgamma ligand rosiglitasone showed only moderate effects. The result of RT-PCR showed that cultured human aortic endothelial cells (HAECs) constitutively express the exclusive receptor for FKN, CX3CR1. When HAECs were subjected to cyclic mechanical stretch (24%, 1 Hz for 30 minutes to 24 hours) using the computer-controlled Flexcell Strain system, the amount of CXCR1 transcripts was significantly increased. Immunohistochemical staining of human in atherosclerotic plaque showed that FKN is expressed on vasa vasorum. CONCLUSION : FKN may play an important role in the formation of ahteromatous plaque as an angiogenic mediator, as well as a chemoattractant and adhesion molecule.