Functional roles for intestinal vasculature in promoting nutrient absorption. (A) Villus blood capillary endothelial cells display small pores, fenestrations, which promote rapid absorption of nutrients transported through the epithelium. High levels of villus VEGFA (from epithelial cells and fibroblasts) promote endothelial fenestration. VEGFA signaling is highest at the villus tip, and VEGFA protein and fenestrations are polarized to the epithelial side of endothelial cells (ECs). VEGFA blockade restricts fenestrations and EC nuclear polarization, making vessels less permeable. VTTs also promote polarized EC fenestration. These fibroblasts uniquely express the metalloprotease ADAMTS18, which degrades fibronectin, thus constraining VEGFA to the epithelial side of ECs. In the absence of VTTs or ADAMTS18, villus tip fibronectin accumulates and spreads bound VEGFA, thereby promoting widespread vessel fenestration and leakiness. (B) Lacteal cell–cell junction status controls dietary fat absorption. Enterocytes package dietary fat into lipoprotein particles called chylomicrons, which are size excluded from blood capillaries. Chylomicrons enter the lymphatic system through open button junctions between lacteal LECs. Increased VEGFC/VEGFR3 or VEGFA/VEGFR2 signaling or loss of Notch signaling leads to zippering of LEC junctions and decreased chylomicron absorption.