Retinal Endothelial Angiogenic Activity: Effects of Hypoxia and Glial (Müller) Cells

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Abstract
Objective: To explore the impact of retinal glial (Müller) cells on survival and neovascularization‐related activities of cultured retinal endothelial cells under normoxic and hypoxic conditions. Methods: Bovine retinal endothelial cells (BRECs) were cultured under normoxia or hypoxia (0.5% O2) either alone, together with the human Müller cell line MIO‐M1, or in normoxia‐ or hypoxia‐conditioned media of MIO‐M1 cells. Cell number, proliferation, apoptotic cell death, and migration of BRECs were determined. Results: Exposure of BRECs to hypoxia for 24 h decreased the number of adherent cells and the proliferation rate, but increased apoptosis and cell migration. Increased apoptosis and decreased proliferation of the BRECs occurred also in the presence of conditioned media of MIO‐M1 cells. Under normoxic conditions, co‐culture with MIO‐M1 cells resulted in increased proliferation, but decreased apoptosis and migration rates of BRECs. Under hypoxic conditions, the Müller cells released elevated amounts of VEGF but their presence decreased proliferation, apoptosis and the migration rates of BRECs. Conclusions: Hypoxia inhibits the proliferation of retinal endothelial cells. Müller cells release soluble mediators that enhance this hypoxia‐mediated effect but, under certain conditions (i.e., in co‐culture), may protect retinal endothelial cells from apoptosis, thus supporting their survival. Altogether the findings indicate that the key signal necessary to trigger retinal endothelial proliferation under hypoxia remains to be determined.