Invited commentary

Abstract

Dr Edwards and colleagues have detailed the in vivo angiogenic potential of an engineered stromal cell-derived factor-1α (SDF) in a rat arterial ligation model. SDF is a powerful chemoattractant of endothelial progenitor cells (EPCs), which represent a cornerstone of the response to ischemia and angiogenesis. Several studies have highlighted the therapeutic role of SDF to increase migration of EPCs and activation of EPCs, to improve healing of diabetic wounds, and to improve angiogenesis and ventricular physiology in cardiac models. A major hurdle to translation of SDF clinically has been the susceptibility to protease degradation and a complex tertiary structure that limits cost-effective production. Gene delivery approaches to overcome these issues add orders of magnitude to the complexity of potential SDF therapies in terms of vector toxicity and regulation of gene expression. The distinctive aspect of this study by Edwards et al is the use of an engineered SDF analog (ESA) peptide that mimics the physiologic properties of recombinant SDF but at a fraction of the size. The authors found that administration of ESA resulted in increased vascular endothelial growth factor expression, capillary density, and limb perfusion over a clinically relevant interval of 14 days. A significant limitation of this study was the administration of the cytokine granulocyte-macrophage colony-stimulating factor (GMCSF) to upregulate bone marrow EPCs in all study groups. Although GMCSF alone has not been shown to improve perfusion without a chemotactic agent such as SDF, the prospective administration of GMCSF clinically represents a significant additional therapeutic for eventual clinical translation. If future studies can demonstrate that ESA mediates angiogenesis independent of GMCSF, this would significantly improve the appeal of engineered SDF. Also, as noted by the authors, they used a model of acute rather than the intended clinical application of chronic ischemia. Potentially, mechanisms of EPC recruitment and the effect of SDF therapies might differ between these two scenarios. Although angiogenic therapies are unlikely to replace current macrovascular open and endovascular surgical approaches, they will be especially useful in scenarios where distal outflow has been compromised by conditions such as diabetes or chronic distal embolism, for instance. Broadly, these therapies should improve distal tissue perfusion and offer additional applications in coronary ischemia. The findings of this study are compelling and represent a meaningful step toward the frontier of angiogenic therapy in peripheral vascular disease. Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limbJournal of Vascular SurgeryVol. 64Issue 4PreviewDespite promising therapeutic innovation over the last decade, peripheral arterial disease remains a prevalent morbidity, as many patients are still challenged with peripheral ischemia. We hypothesized that delivery of engineered stromal cell-derived factor 1-alpha (ESA) in an ischemic hind limb will yield significant improvement in perfusion. Full-Text PDF Open Archive