허혈성 망막병증에서의 metformin의 효과 : Effect of Metformin on Oxygen Induced Retinopathy
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Abstract Purpose: The goal of this study was to evaluate the effect of metformin on vessel growth using oxygen induced retinopathy (OIR) mouse model and human umbilical vein endothelial cell (HUVEC) culture. Methods: OIR mice were treated with intraperitoneal injection of 120mg/kg metformin/day from postnatal day 12 (P12) to P17 or P21. Whole eye globes were harvested at P17 and P21. Vessel formation and avascular area were assessed using retinal flat mounts from OIR mouse eye. Expression of vascular endothelial growth factor (VEGF) was evaluated with enzyme-linked immunosorbent assay (ELISA). The expression of Flk1 and pFlk1 in OIR mouse retina was evaluated with immunohistochemistry. The effect of metformin on the VEGF-induced proliferation of HUVEC was assessed. In addition, the metformin effect on the expression levels of Flk1 and pFlk1 were also measured by Western blots Results: Mice from three groups (control group; vehicle treated OIR group; metformin treated OIR group) were analyzed. There was no difference in the degree of avascular area between metformin-treated OIR mouse retina and vehicle-treated at P17. However, at P21, while the vehicle treated group showed marked improvements in OIR pathology, in the metformin group, OIR pathology still remained. Whereas VEGF expression levels between metformin and vehicle groups did not differ at P17 and P21, the level of Flk-1 appeared significantly reduced in the metformin group as compared with vehicle controls. Consistent with the idea that metformin inhibited vascular growth by reducing Flk1 levels, in HUVEC cultures, it inhibited VEGF-induced cell proliferation, and diminished levels of Flk1 and pFlk1. Conclusion: Metformin has anti-angionenetic effect and delays the normalization of OIR in mouse likely by reducing the level of Flk1, a VEGF receptor.