Gene transfer of stromal cell-derived factor-1α enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: Next-generation chemokine therapy for therapeutic neovascularization

• Published in: Circulation (New York, N.Y.) N.Y.), 2004-05, Vol.109 (20), p.2454-2461
• Main Authors: HIASA, Ken-Ichi, ISHIBASHI, Minako, OHTANI, Kisho, INOUE, Shujiro, QINGWEI ZHAO, KITAMOTO, Shiro, SATA, Masataka, ICHIKI, Toshihiro, TAKESHITA, Akira, EGASHIRA, Kensuke
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Coronary heart disease; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fundamental and applied biological sciences. Psychology; Heart; Medical sciences; Vertebrates: cardiovascular system
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000128213.96779.61

Background— Stromal cell–derived factor-1α (SDF-1α) is implicated as a chemokine for endothelial progenitor cells (EPCs). We therefore hypothesized that SDF-1α gene transfer would induce therapeutic neovascularization in vivo by functioning as a chemokine of EPC. Methods and Results— To examine SDF-1α–induced mobilization of EPC, we used bone marrow–transplanted mice whose blood cells ubiquitously express β-galactosidase (LacZ). We produced unilateral hindlimb ischemia in the mice and transfected them with plasmid DNA encoding SDF-1α or empty plasmids into the ischemic muscles. SDF-1α 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-1α induced vasculogenesis and angiogenesis. SDF-1α 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-1α–induced effects. Conclusions— SDF-1α 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.