Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb Bryan B. Edwards, BE, Alexander S.

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Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb Bryan B. Edwards, BE, Alexander S. Fairman, BA, Jeffrey E. Cohen, MD, John W. MacArthur, MD, Andrew B. Goldstone, MD, Jeffrey B. Woo, William Hiesinger, MD, Y. Joseph Woo, MD Journal of Vascular Surgery Volume 64, Issue 4, Pages 1093-1099 (October 2016) DOI: 10.1016/j.jvs.2015.06.140 Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 1 Crystallographic structural representation of stromal cell-derived factor 1-alpha (SDF-1α) and engineered stromal cell-derived factor 1-alpha (ESA). The N terminal (green), central region (yellow), and C terminal (magenta) are denoted by their respective colors. The central β-sheet region (yellow) in SDF-1α is replaced by a diproline linker in ESA. The corresponding amino acid sequence of each molecule is also depicted and colored according to region. (Reprinted with permission from Hiesinger W, Perez-Aguilar JM, Atluri P, Marotta NA, Frederick JR, Fitzpatrick JR 3rd, et al. Computational protein design to reengineer stromal cell-derived factor-1α generates an effective and translatable angiogenic polypeptide analog. Circulation 2011;124(11 Suppl):S18-26.) Journal of Vascular Surgery 2016 64, 1093-1099DOI: (10.1016/j.jvs.2015.06.140) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 2 Capillary density stratified by treatment group. A, Ligated hind limb samples were cryosectioned and stained for von Willebrand Factor (vWF), smooth muscle actin (SMA), and 4',6-diamidino-2-phenylindole (DAPI). The engineered stromal cell-derived factor 1-alpha (ESA)/granulocyte macrophage colony-stimulating factor (GMCSF) group exhibited a significantly higher mean capillary density (n = 12; 18.55 ± 5.30) than that of the saline/GMCSF group (n = 9; 6.40 ± 2.01; *P < .01). The error bars denote standard error (SE). B, Representative fluorescent microscopy images of quadriceps sections at 10× magnification. Bar = 100 μm. Journal of Vascular Surgery 2016 64, 1093-1099DOI: (10.1016/j.jvs.2015.06.140) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 3 Graph showing vascular endothelial growth factor-A (VEGF-A)-mRNA fluorescence ratio after normalizing to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Flourescence was measured in both quadricep and calf samples. The engineered stromal cell-derived factor 1-alpha (ESA)/granulocyte macrophage colony-stimulating factor (GMCSF)-treated group showed significantly higher fluorescence ratios in both the quad and calf (n = 8; Quad, 0.456 ± 0.139; Calf, 0.473 ± 0.106) relative to the saline/GMCSF group (n = 6; Quad, 0.298 ± 0.205; Calf, 0.285 ± 0.136; *P = .03, **P = .04). The error bars denote standard error (SE). Journal of Vascular Surgery 2016 64, 1093-1099DOI: (10.1016/j.jvs.2015.06.140) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 4 mRNA levels of pro-inflammatory markers in quadriceps of ischemic limbs in both treatment groups. There was minimal difference between engineered stromal cell-derived factor 1-alpha (ESA)/granulocyte macrophage colony-stimulating factor (GMCSF) and saline/GMCSF groups. The error bars denote standard error (SE). GAPDH, Glyceraldehyde 3-phosphate dehydrogenase. *P = .025. Journal of Vascular Surgery 2016 64, 1093-1099DOI: (10.1016/j.jvs.2015.06.140) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 5 A, Representative laser Doppler images of the preoperative hind limb and again at the study endpoint for each group. B, Graph depicting the ratio of perfusion in the ischemic hind limb relative to the nonligated hind limb preoperatively and at three time points after induced ischemia. The engineered stromal cell-derived factor 1-alpha (ESA)/granulocyte macrophage colony-stimulating factor (GMCSF) group (n = 12; 0.900 ± 0.181) showed marked perfusion augmentation by Day 14 relative to that of the saline/GMCSF group (n = 9; 0.600 ± 0.140; group effect P = .006; time effect P < .0001; group×time effect P < .0001). The error bars denote standard error (SE). Journal of Vascular Surgery 2016 64, 1093-1099DOI: (10.1016/j.jvs.2015.06.140) Copyright © 2016 Society for Vascular Surgery Terms and Conditions