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

Abstract

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.

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

“…Enforced release of SDF-1 locally in ischemic tissue leads to increased EPC mobilization and induction of neo-angiogenesis. Of note, those effects are abrogated in the absence of injury, suggesting that other signals emitted by damaged tissue are required for the incorporation of EPCs in the vascular niche within tissues [29,30]. Moreover, implantation of SDF-1-overexpressing cardiac fibroblasts leads to significant revascularization and cardiac functions [14].…”

“…SDF-1 and VEGF-A could converge chemotactic signals to attract VEGFR2 + and CXCR4 + cells, two cell populations that are not totally overlapping in their phenotype and angiogenic properties (Box 1). Increased expression of SDF-1 in the tissue is rapidly followed by its release into the circulation [18,29]. In vitro, SDF-1 is a chemoattractant for EPCs in addition to hematopoietic CXCR4 + cells.…”

Ex vivo delivered stromal cell-derived factor-1α promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium

“…SDF-1α protein and gene delivery to the ischemic heart promotes endothelial progenitor cells recruitment into the ischemic myocardium to promote angiogenesis [1,2,3]. SDF-1α specifically interacts with the CXCR4 receptor and orchestrates the mobilization and homing of hematopoietic stem cells from bone marrow (BM) to the ischemic heart [3][4][5][6].…”

“…SDF-1α specifically interacts with the CXCR4 receptor and orchestrates the mobilization and homing of hematopoietic stem cells from bone marrow (BM) to the ischemic heart [3][4][5][6]. Physiologically, BM harbors a heterogenous population of cells positive for CXCR4 receptor.…”

“…In order to overcome this deficiency, SDF-1α concentration gradient in favor of myocardial scar has been achieved by the delivery of SDF-1α protein or gene encoding for hSDF-1α. The delivery strategies include intramyocardial injection of SDF-1α protein [2], naked plasmid encoding for SDF-1α [3,5,6], transplantation of ex vivo genetically manipulated cardiac fibroblasts overexpressing SDF-1α [4] and mesothelial cell transplantation which intrinsically express copious amounts of SDF-1α [1,14]. Moreover, intramuscular injections of GCSF (Filgrastim) 4 , the sulfated polysaccharide (Fucoidan) [15][16] or "3 hydroxy-3-methylglutaryl-CoA reductase inhibitor" (Atorvastatin) [17][18] have been reported to increase the plasma concentration of hSDF-1α to a level sufficient enough to induce mobilization of stem cells from BM and their homing into the injured tissue.…”