Inhibition of Wnt Inhibitory Factor I Under Hypoxic Condition in Human Umbilical Vein Endothelial Cells Promoted Angiogenesis in Vitro

Placentation is a complicated process critical for maternal–fetal exchange of nutrients and gases that includes stepwise vasculogenesis and angiogenesis. Wnt inhibitory factor I (WIFI) is a secreted Wnt antagonist that acts as a tumor-suppressor gene by antagonizing angiogenesis and proliferation and inducing apoptosis. The purpose of this study was to investigate the function of WIFI on placental angiogenesis in human umbilical vein endothelial cells (HUVECs) under hypoxic conditions. We found that WIFI was diversely expressed in placental vascular endothelial cells at different points during gestation and was weaker in the early placenta than in the term placenta. We validated the antiangiogenesis role of WIFI by inhibiting proliferation, tube formation and migration, and inducing apoptosis of endothelial cells through antagonizing Wnt/β-catenin signaling pathway. We also identified that hypoxic conditions similar to the early placenta inhibited the expression of WIFI and reversed the antiangiogenesis of WIFI in HUVECs. In conclusion, our present study supported the hypothesis that WIFI is crucial as a negative regulator of the functions of endothelial cells in angiogenesis and that hypoxia plays an important role in controlling WIFI expression and angiogenesis. We also demonstrated that Wnt/β-catenin signaling pathway was activated in correspondence with the suppression of WIFI in the angiogenesis of endothelial cells under hypoxic conditions. Keywords hypoxia, angiogenesis, Wnt inhibitory factor I, human umbilical vein endothelial cells