Abstract
BackgroundEndothelial dysfunction has been suggested as a possible causal link between hyperglycemia and microvascular complications in diabetes mellitus. The effect of metformin on endothelial progenitor cells (EPCs) is still unclear. This study was designed to test the hypothesis that metformin could accelerate wound healing by improving the impaired EPC functions in streptozotocin-induced diabetic mice.MethodsStreptozotocin (STZ, 60 mg/kg/d × 5 d, i.p.) was injected to induce type 1 diabetes in male C57BL/6 mice. Mice were treated with metformin (250 mg/kg/d, i.g.) for consecutive 14 days. Wound closure was evaluated by wound area and number of CD31 stained capillaries. Functions of bone marrow-endothelial progenitor cells (BM-EPCs) were assessed by tube formation and migration assays, and expression of AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) was determined by western blot analysis.ResultsMetformin accelerated wound closure and stimulated angiogenesis in diabetic mice. The number of circulating EPCs was increased significantly in metformin treated diabetic mice. Abilities of tube formation and migration of BM-EPCs were impaired in diabetic mice, which were improved by metformin. Expression of both phosphorylated-AMPK and phosphorylated-eNOS was significantly increased, and nitric oxide (NO) production was enhanced by metformin in BM-EPCs of diabetic mice. In vitro, metformin improved impaired BM-EPC functions, and increased phosphorylated-eNOS expression and NO production in cultured BM-EPCs caused by high glucose, which was prevented by the AMPK inhibitor compound C.ConclusionsOur results suggest that metformin could improve BM-EPC functions in STZ-induced diabetic mice, which was possibly dependent on the AMPK/eNOS pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0408-3) contains supplementary material, which is available to authorized users.
Highlights
Endothelial dysfunction has been suggested as a possible causal link between hyperglycemia and microvascular complications in diabetes mellitus
Metformin accelerated wound closure and angiogenesis in diabetic mice To assess the effects of metformin on wound healing in STZ-induced diabetic mice, the percentage of wound closure was measured every other day until day 10
In the present study, we found that: (1) metformin accelerated wound healing and stimulated angiogenesis, improved the impaired Endothelial progenitor cells (EPCs) capacity, and increased nitric oxide (NO) production in bone marrow-endothelial progenitor cells (BM-EPCs) of STZ-induced diabetic mice; (2) In vitro, metformin improved high glucose-impaired EPC function, and enhanced intracellular NO level; (3) the protective effects of metformin on BM-EPCs were possibly related to activating AMP-activated protein kinase (AMPK)/endothelial nitric oxide synthase (eNOS) pathway
Summary
Endothelial dysfunction has been suggested as a possible causal link between hyperglycemia and microvascular complications in diabetes mellitus. The effect of metformin on endothelial progenitor cells (EPCs) is still unclear. This study was designed to test the hypothesis that metformin could accelerate wound healing by improving the impaired EPC functions in streptozotocin-induced diabetic mice. Endothelial progenitor cells (EPCs) play a primary role in angiogenesis but are functionally impaired in diabetes, which may contribute to endothelial dysfunction [7]. Studies found that clinically relevant concentrations of metformin activated AMPK in cultured endothelial cells (ECs) [17,18,19,20,21]. Our study tested the hypothesis that metformin could accelerate wound healing, at least in part, by improving the angiogenic functions of EPCs with an AMPK related pathway in diabetic mice
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