Published Online
on May 17, 2004

A more recent version of this article appeared on May 25, 2004

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Submitted on December 15, 2003
Revised on February 6, 2004
Accepted on February 11, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: egashira{at}cardiol.med.kyushu-u.ac.jp.

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 -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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