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

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