Rosiglitazone accelerates wound healing by improving endothelial precursor cell function in db/db mice

Background & Aims. Endothelial precursor cell (EPC) dysfunction is one of the risk factors for diabetes mellitus (DM) which results in delayed wound healing. Rosiglitazone (RSG) is a frequently prescribed oral glucose-lowering drug. Previous studies have shown the positive eﬀects of RSG on ameliorating EPC dysfunction in diabetic patients. Interestingly, knowledge about RSG with regard to the wound healing process caused by DM is scarce. Therefore, in this study, we investigated the possible actions of RSG on wound healing and the related mechanisms involved in db/db diabetic mice. Methods. Db/db mice with spontaneous glucose metabolic disorder were used as a type 2 DM model. RSG (20mg/kg/d, i.g. ) was administered for 4 weeks before wound creation and bone marrow derived EPC (BM-EPC) isolation. Wound closure was assessed by wound area and CD31 staining. Tubule formation and migration assays were used to judge the function of the BM-EPCs. The level of vascular endothelial growth factor (VEGF), stromal cell derived factor-1α (SDF-1α) and insulin signaling was determined by ELISA. Cell viability of the BM-EPCs was measured by CCK-8 assay. Results. RSG signiﬁcantly accelerated wound healing and improved angiogenesis in db/db mice. Bioactivities of tube formation and migration were decreased in db/db mice but were elevated by RSG. Level of both VEGF and SDF-1α was increased by RSG in the BM-EPCs of db/db mice. Insulin signaling was elevated by RSG reﬂected in the phosphorylated-to-total AKT in the BM-EPCs. In vitro , RSG improved impaired cell viability and tube formation of BM-EPCs induced by high glucose, but this was prevented by the VEGF inhibitor avastin. Conclusion. Our data demonstrates that RSG has beneﬁts for wound healing and angiogenesis in diabetic mice, and was partially associated with improvement of EPC function through activation of VEGF and stimulation of SDF-1α in db/db mice. Abstract cell (EPC) dysfunction diabetes mellitus (DM) which results in delayed wound healing. Rosiglitazone (RSG) is a 39 frequently prescribed oral glucose-lowering drug. Previous studies have shown the positive 40 effects of RSG on ameliorating EPC dysfunction in diabetic patients. Interestingly, knowledge 41 about RSG with regard to the wound healing process caused by DM is scarce. Therefore, in this study, we investigated the possible actions of RSG on wound healing and the related 43 mechanisms involved in db/db diabetic mice. Methods. Db/db mice with spontaneous glucose metabolic disorder were used as a type 2 DM 45 model. RSG (20mg/kg/d, i.g. ) was administered for 4 weeks before wound creation and bone 46 marrow derived EPC (BM-EPC) isolation. Wound closure was assessed by wound area and 47 CD31 staining. Tubule formation and migration assays were used to judge the function of the 48 BM-EPCs. The level of vascular endothelial growth factor (VEGF), stromal cell derived factor-49 1α (SDF-1α) and insulin signaling was determined by ELISA. Cell viability of the BM-EPCs 50 was measured by CCK-8 assay. 51 Results. RSG significantly accelerated wound healing and improved angiogenesis in db/db mice. RSG. and was partially associated with improvement of EPC function through activation of VEGF and stimulation of SDF-1α in db/db mice. sensitivity 2013). Several beneficial effects of RSG on EPCs been convincingly described. In vitro findings support RSG's attenuation of EPC dysfunction and apoptosis, and the related signaling pathways are involved in ERK/MAPK, NF-κB and Akt-96 eNOS of EPCs (Sheng 2011; Chun et al., 2009). In addition, clinical research suggests that RSG treatment for 12 weeks improves EPC amounts and migratory ability in patients with Abstract