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Jing Han, Xiuli Liu, Tongrong Zhou, Paul A Edwards, Hua Gao, Xiaoxi Qiao; Metformin Inhibits Angiogenesis of Human Retinal Vascular Endothelial Cells in vitro and in vivo. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1964.
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Metformin, a drug used to treat Type II diabetes mellitus, has recently been found to reduce cardiovascular complications of diabetes, independent of its glucose-lowering effect. The purpose of this study was to investigate the potential effect of metformin on human retinal microvascular endothelial cells (hRVECs).
Primary human RVECs(ACBRI 181) were used for all in vitro assays. Cells were treated with various dosages of metformin. Cell viability, proliferation, migration, and capillary formation were assessed by viable cell quantification, MTS assay, scratch assay, and matrigel tube formation assay. The cell apoptosis was determined by TUNEL assay. Matrigel plug assay was performed in C57BL6 mice with or without oral metformin administration.
Metformin at the range of 5~50mM elicited significant inhibition on hRVECs in all of these in vitro angiogenic assays in a dose-dependent manner. Proliferation of hRVECs was significantly inhibited by over 20% starting at 5mM metformin treatment (p <0.01), and the cell metabolic rate was significantly reduced in MTS assay at 40mM or higher (p <0.01). Metformin attenuated hRVEC migration in the scratch assay at 20mM and above. Tube formation assay appears to be the most sensitive one with a statistically significant reduction of total tube length starting at 10mM metformin (p<0.05). Meanwhile, no apoptotic hRVEC cells were observed in any of these doses. Preliminary in vivo matrigel plug assay revealed 50% reduction of capillary infiltration into the matrigel plugs in mice treated with systemic metformin when compared to that of the vehicle control.
These results demonstrate that metformin has direct inhibitory effects on human RVEC angiogenesis in vitro, and that metformin’s anti-angiogenic effect is also confirmed in vivo. These findings provide direct support of metformin treatment benefit for proliferative diabetic retinopathy.
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