Wogonin influences vascular permeability via Wnt/β-catenin pathway

Wogonin, a flavone from the root of Scutellaria baicalensis Georgi, has shown various biological activities. In our previous study, it was confirmed that wogonin could decrease the expression of hypoxia-inducible factor-1α (HIF-1α) by affecting its stability under hypoxia. However, it is still unknown whether wogonin could influence Wnt/β-catenin pathway under hypoxia. In this study, we found that wogonin disrupted Wnt/β-catenin signaling and reduced the secretion of vascular endothelial growth factor (VEGF, also known as vascular permeability factor, VPF), which increased vascular permeability in certain diseases. It was found that wogonin suppressed HUVECs hyperactivity and actin remodeling induced by hypoxia, inhibited transendothelial cell migration of the human breast carcinoma cell MDA-MB-231 and the extravasated Evans in vivo Miles vascular permeability assay. Wogonin-treated cells showed a decrease in the expression of Wnt protein and its co-receptors, as well as a parallel increase in the expression of Axin and GSK-3β in degradation complex, leading to degradation of β-catenin. In addition, wogonin promoted the binding between Axin and β-catenin, increased ubiquitination of β-catenin and promoted its degradation. Interestingly, wogonin decreased the expression of TCF-1, TCF-3, and LEF-1 and inhibited nuclear accumulation of β-catenin as well as the binding of β-catenin and TCF-1, TCF-3, or LEF-1. All of the above results showed that wogonin could inhibit the expression of VEGF, which is an important factor regulated by β-catenin. Taken together, the results suggested that wogonin was a potent inhibitor of Wnt/β-catenin and influenced vascular permeability, and this might provide new therapeutics in certain diseases.