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(Circulation. 2004;109:2454-2461.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Gene Transfer of Stromal Cell–Derived Factor-1 Enhances Ischemic Vasculogenesis and Angiogenesis via Vascular Endothelial Growth Factor/Endothelial Nitric Oxide Synthase–Related Pathway

Next-Generation Chemokine Therapy for Therapeutic Neovascularization

Ken-ichi Hiasa, MD; Minako Ishibashi, MD; Kisho Ohtani, MD; Shujiro Inoue, MD; Qingwei Zhao, MD; Shiro Kitamoto, MD; Masataka Sata, MD; Toshihiro Ichiki, MD; Akira Takeshita, MD; Kensuke Egashira, MD

From the Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka (K.H., M.I., K.O., S.I., Q.Z., S.K., T.I., A.T., K.E.), and the Department of Cardiovascular Medicine, Tokyo University Graduate School of Medical Sciences, Tokyo (M.S.), Japan.

Correspondence to Kensuke Egashira, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp

Received December 15, 2003; revision received February 6, 2004; accepted February 11, 2004.

Background— Stromal cell–derived factor-1 (SDF-1) is implicated as a chemokine for endothelial progenitor cells (EPCs). We therefore hypothesized that SDF-1 gene transfer would induce therapeutic neovascularization in vivo by functioning as a chemokine of EPC.

Methods and Results— To examine SDF-1–induced mobilization of EPC, we used bone marrow–transplanted mice whose blood cells ubiquitously express ß-galactosidase (LacZ). We produced unilateral hindlimb ischemia in the mice and transfected them with plasmid DNA encoding SDF-1 or empty plasmids into the ischemic muscles. SDF-1 gene transfer mobilized EPCs into the peripheral blood, augmented recovery of blood perfusion to the ischemic limb, and increased capillary density associated with partial incorporation of LacZ-positive cells into the capillaries of the ischemic limb, suggesting that SDF-1 induced vasculogenesis and angiogenesis. SDF-1 gene transfer did not affect ischemia-induced expression of vascular endothelial growth factor (VEGF) but did enhance Akt and endothelial nitric oxide synthase (eNOS) activity. Blockade of VEGF or NOS prevented all such SDF-1–induced effects.

Conclusions— SDF-1 gene transfer enhanced ischemia-induced vasculogenesis and angiogenesis in vivo through a VEGF/eNOS-related pathway. This strategy might become a novel chemokine therapy for next generation therapeutic neovascularization.

Key Words: angiogenesis • gene therapy • nitric oxide synthase • ischemia

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