Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 11, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm067
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Activation of Fractalkine/CX3CR1 by Vascular Endothelial Cells Induces Angiogenesis through VEGF-A/KDR and Reverses Hindlimb Ischemia
a Division of Cardiology, Department of Internal Medicine
b Department of Pathology
c Department of Anesthesiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Address correspondence to: Ki Hoon Han, University of Ulsan, College of Medicine, Asan Medical Center, 388-1 Pungnap-2 dong Songpa-gu 138-736, Seoul, South Korea, Tel: 82-2-3010-3150, Fax: 82-2-486-5918, E-mail: steadyhan{at}amc.seoul.kr
Aims: The present study investigated the detailed mechanism by which fractalkine (Fkn), a CX3C chemokine, induces angiogenesis and its functional implication in alleviating ischemia in vivo.
Methods and Results: Fkn induced new vessel formation on the excised rat aorta and chick chorioallantoic membrane (CAM) through CX3CR1 activation. Immunoblotting analysis, promoter assay and electrophoretic mobility shift assay showed that Fkn upregulated hypoxia-inducible factor-1 alpha (HIF-1
) by cultured human aortic endothelial cells (HAECs), which in turn induced mRNA and protein levels of vascular endothelial growth factor (VEGF)-A through a p42/44 mitogen-activated protein (MAP) kinase pathway. In vivo Fkn-induced angiogenesis on CAM was completely blocked by functional inhibition of VEGF receptor 2 (KDR) and Rho GTPase. C57/BL6 mice with CX3CR1(-/-) bone marrow-derived cells developed angiogenesis in the implanted Fkn-mixed Matrigel plug, suggesting CX3CR1 activation in vascular endothelial cells (ECs) is sufficient for Fkn-induced angiogenesis in vivo. The condition of rat hindlimb ischemia, which rapidly stimulated mRNA expression of both Fkn and VEGF-A, was significantly alleviated by the injection of whole-length Fkn protein.
Conclusions: Fkn-induced activation of CX3CR1 by ECs leads to in vivo angiogenesis through two sequential steps: the induction of HIF-1 and VEGF-A gene expression by CX3CR1 activation and the subsequent VEGF-A/KDR-induced angiogenesis. The potent induction of angiogenesis by Fkn can be used as a therapeutic strategy for alleviating peripheral ischemia.
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