Figure 8 of Cammarata, Mol Vis 2015; 21:1024-1035.

Figure 8. Schematic representation of the role of hypoxia inducible factor-1α or β-catenin on the regulation of expression of epithelial to mesenchymal transition early marker proteins and VEGF synthesis. Atmospheric oxygen: Catalytic activity of glycogen synthase kinase-3β (GSK-3β) is blocked using the specific GSK-3β inhibitor, SB216763. Inhibition of GSK-3β activity prevents the phosphorylation of β-catenin. Non-phosphorylated β-catenin translocates to the nucleus. Nuclear β-catenin acts as transcription factor in two independent pathways leading to [1]; elevated synthesis and accumulation of fibronectin and alpha smooth muscle actin (α-SMA) and [2] elevated synthesis of the prosurvival protein, vascular endothelial growth factor (VEGF). Increased accumulation of fibronectin and α-SMA is an early marker indicator for epithelial to mesenchymal transition, which in the lens is a contributing factor to posterior capsular opacification. At the same time, increased accumulation of VEGF promotes cell survival via the prevention of mitochondrial depolarization and cell death. Although present in the cell, hypoxia-inducible factor-2α (HIF-2α) plays no discernible role in these pathways under atmospheric oxygen conditions. Hypoxia: HIF-1α intracellular levels are decreased using the specific HIF-1α translation inhibitor KC7F2. The resulting inhibition of the transcription factor HIF-1α suppresses the synthesis of fibronectin and α-SMA, thus minimizing the trend toward epithelial to mesenchymal transition. Because of the cooperation between HIF-1α and HIF-2α under hypoxic conditions, the suppression of HIF-1α is compensated for by HIF-2α resulting in sustained VEGF synthesis and accumulation. Unlike the situation found with atmospheric oxygen, β-catenin appears to play little to no role in these processes.