Endothelial Progenitor Cell-Mediated Angiogenesis is Promoted by the Transforming Growth Factor Beta 1/CXC Chemokine Receptor 7 Signaling Axis in Diabetes Mellitus

Abstract Background The role of the transforming growth factor (TGF)-β1/CXC chemokine receptor (CXCR) 7 signaling axis in angiogenesis mediated by endothelial progenitor cells (EPCs) in diabetes mellitus (DM) remains unclear. Methods An in vivo wound healing model was established in mice, which were treated with phosphate-buffered saline (PBS) or TGF-β1. Wound closure rate was measured to evaluate wound healing. Histological analysis and immunofluorescent staining were performed to investigate angiogenesis and the number of EPCs in vivo. EPCs were isolated from bone marrow via gradient centrifugation. An angiogenic medium was used to induce endothelial cells (ECs) from EPCs. Flow cytometry was used to identify EPCs and ECs. Lv-shCXCR7 was used to determine the role of CXCR7 in EPCs in vitro. EPC proliferation was measured via 5-ethynyl-2′-deoxyuridine staining. Scratch and transwell assays were performed to assess EPC migration. Results Remaining wound area from day 7 to 14 in the DM + TGF-β1 group was significantly lower than that in the DM + PBS group but higher than that in the PBS group. On day 14, the number of microvessels in wounds was significantly higher for TGF-β1-treated mice than for mice not treated with TGF-β1. The number of EPCs in the DM + TGF-β1 group was significantly higher than that in the DM + PBS group. The high-glucose environment significantly impaired the proliferation, migration, and tube-forming ability of EPCs; however, TGF-β1 partially restored the proliferation and tube-forming ability of EPCs (p < 0.05). Additionally, shCXCR7 lentiviral transfection resulted in a significant reduction in the proliferation and tube-forming ability of EPCs; however, it had no significant effect on EPC migration. Furthermore, the high-glucose environment caused a decrease in the mRNA and protein expression of CXCR7 in EPCs; however, this was partially reversed by TGF-β1 (p < 0.05). Conclusions Our results show for the first time that TGF-β1 partially restores the proliferation and tube-forming ability of EPCs in a high-glucose environment by upregulating CXCR7 expression, increasing the number of blood vessels, and accelerating wound healing. This novel TGF-β1 pathway may play a potentially therapeutic role from bench to bedside.