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Despite 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.Male rats underwent right femoral artery ligation, and animals were randomized to receive a 100 μL injection of saline (n = 9) or 6 μg/kg dosage of equal volume of ESA (n = 12) into the ipsilateral quadriceps muscle. Both groups of animals were also given an intraperitoneal injection of 40 μg/kg of granulocyte macrophage colony-stimulating factor (GMCSF). Perfusion was quantified using a laser Doppler imaging device preoperatively, and on postoperative days 0, 7, and 14. Immunohistochemistry was performed to quantify angiogenesis on day 14, and an mRNA profile was evaluated for angiogenic and inflammatory markers.Compared with the saline/GMCSF group at day 14, the ESA/GMCSF-injected animals had greater reperfusion ratios (Saline/GMCSF, 0.600 ± 0.140 vs ESA/GMCSF, 0.900 ± 0.181; group effectP= .006; time effectP< .0001; group×time effectP< .0001), elevated capillary density (10×; Saline/GMCSF, 6.40 ± 2.01 vs ESA/GMCSF, 18.55 ± 5.30;P< .01), and increased mRNA levels of vascular endothelial growth factor-A (Saline/GMCSF [n = 6], 0.298 ± 0.205 vs ESA/GMCSF [n = 8], 0.456 ± 0.139;P= .03).Delivery of ESA significantly improves perfusion in a rat model of peripheral arterial disease via improved neovasculogenesis, a finding which may prove beneficial in the treatment strategy for this debilitating disease.The use of cytokines and growth factors to promote revascularization is a well-studied therapeutic strategy. Previous studies have confirmed the efficacy of stromal cell-derived factor 1-alpha (SDF) in revascularizing both cardiac and peripheral vascular disease models. However, there are limitations associated with using recombinant SDF, including its bulkiness and high cost. This study demonstrates that injection of a bioengineered analog of SDF, engineered stromal cell-derived factor 1-alpha, into an ischemic hind limb is an effective therapy that enhances perfusion. Herein, we describe an extremely clinically translatable peptide therapy utilizing a cost-efficient, smaller protein analog resulting in effective microrevascularization of ischemic muscle.