Inhibition of glycolysis modulates retinal endothelial cell function and pathological neovascularization

Le résumé fourni par la source

In many retinopathies, hypoxia stimulates pathogenic neovascularization. The precise impact of hypoxia and how it may drive a switch in retinal microvascular endothelial cell metabolism during active angiogenesis remains ill-defined. This study has sought to understand dynamic shifts in the metabolic profile of retinal microvascular endothelial cells exposed to hypoxia and during ischemia-induced neovascularization. The impact of manipulating glycolytic metabolism by intravitreal injection of the glycolytic inhibitor 3-(3-Pyridinyl)-1-(4pyridinyl)-2-propen-1-one) (3PO) on pre-retinal neovascularization was investigated using the oxygen-induced retinopathy (OIR) model. Metabolic pathways generating adenosine triphosphate (ATP) in human retinal microvascular endothelial cells (HRMECs) was evaluated using qPCR and the Seahorse XFe96 analyzer under normal culture conditions and hypoxia ± 3PO. The role of glycolysis in HRMEC angiogenesis related processes such as tubulogenesis, proliferation and migration were assessed when glycolysis was blocked by 3PO. Our study showed that intravitreal injection of 3PO in the OIR model inhibited pre-retinal neovascularization compared to vehicle injected controls (P < 0.0001). While hypoxia increased glycolysis in HRMECs, treatment with 3PO reduced their glycolytic activity under normoxia and hypoxia culture conditions. Treatment with 3PO, reduced glycolytic mRNA expression of GLUT1, HK1, PFKFB3, ENO2 and VEGFA. Finally, glycolytic inhibition reduced tubulogenesis (p < 0.05), migratory capacity (p < 0.001) and proliferation (p < 0.01) of HRMECs in vitro. This data suggests that retinal angiogenesis can be modulated by manipulating the glycolytic pathway using 3PO in vivo and that 3PO treatment in vitro can diminish the angiogenic potential of HRMECs.

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