Abstract
PurposeTo evaluate the effect of metformin on vascular changes in oxygen-induced retinopathy (OIR) in mouse, and to elucidate the possible underlying mechanism.MethodsOIR mice were treated with metformin by intraperitoneal injection from postnatal day 12 (P12) to P17 or P21. At P17 and P21, vessel formation and avascular areas were assessed using retinal flat mounts. Levels of vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunosorbent assays, and the effects of metformin on VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) were assessed. The effects of metformin on the levels of Flk1 (VEGF receptor-2) and phosphorylated Flk1 (pFlk1) were measured by Western blotting (HUVECs) and immunohistochemistry (retinal tissue).ResultsRetinal morphologic changes were analyzed between two groups (saline-treated OIR; metformin-treated OIR). Metformin treatment did not change the extent of avascular areas at P17. However, at P21, when OIR pathology was markedly improved in the saline-treated group, OIR pathology still remained in the metformin-treated OIR group. VEGF expression levels did not differ between metformin- and saline-treated OIR groups at P17 and P21, but Flk1 levels were significantly reduced in the metformin group compared with saline-treated OIR group. Moreover, metformin inhibited VEGF-induced cell proliferation and decreased levels of Flk1 and pFlk1, consistent with the interpretation that metformin inhibits vascular growth by reducing Flk1 levels.ConclusionMetformin exerts anti-angiogenesis effects and delays the normal vessel formation in the recovery phase of OIR in mice, likely by suppressing the levels of Flk1.
Highlights
Blood vessels are formed in two different ways: vasculogenesis, which represents vessel formation from progenitor cells, and angiogenesis, which denotes new vessel formation from pre-existing vessels [1]
At P21, when oxygen-induced retinopathy (OIR) pathology was markedly improved in the saline-treated group, OIR pathology still remained in the metformin-treated OIR group
vascular endothelial growth factor (VEGF) expression levels did not differ between metformin- and saline-treated OIR groups at P17 and P21, but Flk1 levels were significantly reduced in the metformin group compared with saline-treated OIR group
Summary
Blood vessels are formed in two different ways: vasculogenesis, which represents vessel formation from progenitor cells (de novo pathway), and angiogenesis, which denotes new vessel formation from pre-existing vessels [1]. Neovascularization is a key pathological contributor to tumor growth and in many retinal diseases. Ischemia may be the central underlying mechanism in retinal diseases involving neovascularization, such as diabetic retinopathy (DR), retinopathy of prematurity (ROP), retinal vein occlusion, retinal arterial occlusion, and ocular ischemic syndrome [2]. The main causes of vision loss in patients with DR are diabetic macular edema (DME) and diabetic vitreous hemorrhage [3,4]. Vitreous hemorrhage originates from new vessels adjacent to ischemic areas [3,4]. Vascular endothelial growth factor (VEGF) has been identified as a critical factor for DR and diabetic macular edema. Anti-VEGF treatment has shown considerable promise in promoting the regression of new retinal vessels and preventing DR progression [3,4,5]
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