The family of vascular endothelial growth factors (VEGFs) includes 5 members (VEGF-A to -D, and placenta growth factor), which regulate several critical biological processes. VEGF-A exerts a variety of biological effects through high-affinity binding to tyrosine kinase receptors (VEGFR-1, -2 and -3), co-receptors and accessory proteins. In addition to its fundamental function in angiogenesis and endothelial cell biology, VEGF/VEGFR signalling also plays a role in other cell types including epithelial cells. This review provides an overview of VEGF signalling in biliary epithelial cell biology in both normal and pathologic conditions. VEGF/VEGFR-2 signalling stimulates bile duct proliferation in an autocrine and paracrine fashion. VEGF/VEGFR-1/VEGFR-2 and angiopoietins are involved at different stages of biliary development. In certain conditions, cholangiocytes maintain the ability to secrete VEGF-A, and to express a functional VEGFR-2 receptor. For example, in polycystic liver disease, VEGF secreted by cystic cells stimulates cyst growth and vascular remodelling through a PKA/RAS/ERK/HIF1α-dependent mechanism, unveiling a new level of complexity in VEFG/VEGFR-2 regulation in epithelial cells. VEGF/VEGFR-2 signalling is also reactivated during the liver repair process. In this context, pro-angiogenic factors mediate the interactions between epithelial, mesenchymal and inflammatory cells. This process takes place during the wound healing response, however, in chronic biliary diseases, it may lead to pathological neo-angiogenesis, a condition strictly linked with fibrosis progression, the development of cirrhosis and related complications, and cholangiocarcinoma. Novel observations indicate that in cholangiocarcinoma, VEGF is a determinant of lymphangiogenesis and of the immune response to the tumour. Better insights into the role of VEGF signalling in biliary pathophysiology might help in the search for effective therapeutic strategies.
Keywords: ADPKD, adult dominant polycystic kidney disease; Anti-Angiogenic therapy; BA, biliary atresia; BDL, bile duct ligation; CCA, cholangiocarcinoma; CCl4, carbon tetrachloride; CLDs, chronic liver diseases; Cholangiocytes; Cholangiopathies; DP, ductal plate; DPM, ductal plate malformation; DRCs, ductular reactive cells; Development; HIF-1α, hypoxia-inducible factor type 1α; HSCs, hepatic stellate cells; IHBD, intrahepatic bile ducts; IL-, interleukin-; LECs, lymphatic endothelial cells; LSECs, liver sinusoidal endothelial cells; Liver repair; MMPs, matrix metalloproteinases; PBP, peribiliary plexus; PC, polycystin; PDGF, platelet-derived growth factor; PIGF, placental growth factor; PLD, polycystic liver diseases; Polycystic liver diseases; SASP, senescence-associated secretory phenotype; TGF, transforming growth factor; VEGF, vascular endothelial growth factors; VEGF-A; VEGF/VEGFR-2 signalling; VEGFR-1/2, vascular endothelial growth factor receptor 1/2; mTOR, mammalian target of rapamycin.
© 2021 The Authors.