Epithelial VEGF signaling is required in the mouse liver for proper sinusoid endothelial cell identity and hepatocyte zonation in vivo.

Vascular endothelial growth factor (VEGF) is crucial for vascular development in several organs. However, the specific contribution of epithelial-VEGF signaling in the liver has not been tested. We used a mouse model to specifically delete Vegf from the liver epithelial lineages during midgestational development and assessed the cell identities and architectures of epithelial and endothelial tissues. We find that without epithelial-derived VEGF, the zonal endothelial and hepatocyte cell identities are altered. We also find decreased portal vein and hepatic artery branching coincident with an increase in hepatic hypoxia postnatally. Together, these data indicate that VEGF secreted from the hepatic epithelium is required for normal differentiation of cells and establishment of three-dimensional vascular branching and zonal architectures in both epithelial and endothelial hepatic tissues.