Cilostazol Improves Proangiogenesis Functions in Human Early Endothelial Progenitor Cells through the Stromal Cell-Derived Factor System and Hybrid Therapy Provides a Synergistic Effect In Vivo

Figure 4

Different treatment strategies in mice with hindlimb ischemia. (a) Representative images of laser Doppler perfusion flow in hindlimbs. Cilostazol, EPC transplantation, and hybrid therapy accelerated flow recovery 14 days after surgery, in particular, with hybrid therapy (a, b). (c) Representative photos of capillaries in the leg muscles visualized by anti-CD31 immunostaining (red) and nuclei counterstained with hematoxylin (blue). Capillary density was significantly higher in EPCs-, cilostazol-, and, notably, combined EPCs and cilostazol-treated mice (d). (e) Measurement of plasma levels of SDF-1α. Plasma SDF-1α levels were significantly higher in all 3 active treatment groups as compared to the vehicle group 48 hours after surgery. However, the greatest effect was achieved and maintained during the 72-hour course in the hybrid group. (f) Quantification of peripheral CD34⁺ cells in mice treated with different therapeutic strategies at different time points. (g) Phosphorylation of Akt/eNOS signaling molecules and expression of SDF-1α/CXCR4 proteins. Active treatments, especially hybrid therapy, could upregulate SDF-1α/CXCR4/Akt/eNOS molecules in ischemic hindlimbs. , , and , significantly different compared with vehicle-treated mice. CXCR4, C-X-C chemokine receptor type 4; eNOS, endothelial nitric oxide synthase; EPCs, endothelial progenitor cells; NL, nonligated; SDF-1α, stromal cell-derived factor-1α.

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