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.