Mangiferin inhibits cell migration and angiogenesis via PI3K/AKT/mTOR signaling in high glucose- and hypoxia-induced RRCECs

Mangiferin is a prominent active component that can be derived from several traditional herbs, including Mangifera indica L., Anemarrhena asphodeloides Bge., and Belamcanda chinensis (L.) DC., which displays antidiabetic properties. Diabetic retinopathy (DR), a serious complication caused by diabetes, is the leading cause of blindness. The present study aimed to evaluate the beneficial effects of mangiferin on high glucose (HG)/hypoxia-induced rat retinal capillary endothelial cell (RRCEC) angiogenesis, as well as the underlying mechanisms. To establish an in vitro model of DR, RRCECs were exposed to 30 mM glucose and hypoxia. Following treatment with different doses of mangiferin (0.05, 0.1 or 0.2 µM), RRCEC viability, migration and angiogenesis were assessed by performing Cell Counting Kit 8, immunofluorescence, wound healing, Transwell and tube formation assays. Western blotting was conducted to evaluate protein expression levels. Furthermore, LY294002 and IGF-1, an inhibitor and activator of the PI3K/AKT/mTOR signaling pathway, respectively, were used to verify the potential mechanisms underlying mangiferin. The results demonstrated that mangiferin notably inhibited HG/hypoxia-induced RRCEC migration and angiogenesis. HG/hypoxia-induced upregulation of hypoxia-inducible factor-1α, vascular endothelial growth factor, matrix metallopeptidase (MMP)2 and MMP9 expression levels and the phosphorylation of PI3K, AKT and mTOR in RRCECs was significantly reversed following treatment with mangiferin. Additionally, further activation of the PI3K/AKT signaling pathway by IGF-1 inhibited the beneficial effects of mangiferin on RRCECs, whereas deactivation of the PI3K/AKT signaling pathway by LY294002 displayed the opposite results. Collectively, the results of the present study suggested that mangiferin suppressed RRCEC angiogenesis via modulating the PI3K/AKT/mTOR signaling pathway, which could serve as an effective treatment strategy for DR.