Inhibition of glycolysis modulates retinal endothelial cell function and pathological neovascularization

Area of Science:

• Ophthalmology
• Cell Biology
• Metabolic Research

Background:

• Hypoxia is a key driver of pathological neovascularization in retinopathies.
• The metabolic shifts in retinal microvascular endothelial cells during angiogenesis are not fully understood.

Purpose of the Study:

• To investigate metabolic changes in retinal microvascular endothelial cells under hypoxia.
• To assess the impact of inhibiting glycolysis with 3PO on neovascularization in the oxygen-induced retinopathy (OIR) model.

Main Methods:

• Evaluated ATP generation pathways in human retinal microvascular endothelial cells (HRMECs) using qPCR and Seahorse XFe96.
• Assessed the role of glycolysis in HRMEC angiogenesis (tubulogenesis, proliferation, migration) with 3PO.
• Administered intravitreal 3PO in the OIR mouse model.

Main Results:

• Intravitreal 3PO injection significantly inhibited pre-retinal neovascularization in the OIR model.
• Hypoxia increased glycolysis in HRMECs, while 3PO reduced glycolytic activity under normoxia and hypoxia.
• 3PO treatment decreased mRNA expression of key glycolytic genes (GLUT1, HK1, PFKFB3, ENO2, VEGFA).
• Glycolytic inhibition by 3PO reduced HRMEC tubulogenesis, migration, and proliferation in vitro.

Conclusions:

• Retinal angiogenesis can be modulated by targeting the glycolytic pathway with 3PO in vivo.
• 3PO diminishes the angiogenic potential of HRMECs by inhibiting glycolysis.