New insights on the role of vascular endothelial growth factor in biliary pathophysiology.

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.

Biliary tract anatomy and its relationship with venous drainage.

Portal cavernoma develops as a bunch of hepatopetal collaterals in response to portomesenteric venous obstruction and induces morphological changes in the biliary ducts, referred to as portal cavernoma cholangiopathy. This article briefly reviews the available literature on the vascular supply of the biliary tract in the light of biliary changes induced by portal cavernoma. Literature pertaining to venous drainage of the biliary tract is scanty whereas more attention was focused on the arterial supply probably because of its significant surgical implications in liver transplantation and development of ischemic changes and strictures in the bile duct due to vasculobiliary injuries. Since the general pattern of arterial supply and venous drainage of the bile ducts is quite similar, the arterial supply of the biliary tract is also reviewed. Fine branches from the posterior superior pancreaticoduodenal, retroportal, gastroduodenal, hepatic and cystic arteries form two plexuses to supply the bile ducts. The paracholedochal plexus, as right and left marginal arteries, run along the margins of the bile duct and the reticular epicholedochal plexus lie on the surface. The retropancreatic, hilar and intrahepatic parts of biliary tract has copious supply, but the supraduodenal bile duct has the poorest vascularization and hence susceptible to ischemic changes. Two venous plexuses drain the biliary tract. A fine reticular epicholedochal venous plexus on the wall of the bile duct drains into the paracholedochal venous plexus (also called as marginal veins or parabiliary venous system) which in turn is connected to the posterior superior pancreaticoduodenal vein, gastrocolic trunk, right gastric vein, superior mesenteric vein inferiorly and intrahepatic portal vein branches superiorly. These pericholedochal venous plexuses constitute the porto-portal collaterals and dilate in portomesenteric venous obstruction forming the portal cavernoma.

Vascular biology of the biliary epithelium.

Cholangiocytes are involved in a variety of processes essential for liver pathophysiology. To meet their demanding metabolic and functional needs, bile ducts are nourished by their own arterial supply, the peribiliary plexus. This capillary network originates from the hepatic artery and is strictly arranged around the intrahepatic bile ducts. Biliary and vascular structures are linked by a close anatomic and functional association necessary for liver development, normal organ physiology, and liver repair. This strong association is finely regulated by a range of angiogenic signals, enabling the cross talk between cholangiocytes and the different vascular cell types. This review will briefly illustrate the "vascular" properties of cholangiocytes, their underlying molecular mechanisms and the relevant pathophysiological settings.

Morphological Changes of Hepatic Microcirculation in N-diethylnitrosamine Induced Cirrhotic Rat Liver

Morphological changes of hepatic microcirculation, especially in the peribiliary plexus, in cirrhotic livers of rats induced by repeated intraperitoneal injections of N-diethyinitrosamine (DEN) (100mg/kg/week) were studied by scanning electron microscopy. Control rats were treated with saline. The livers were perfused with saline and injected with methyl-methacrylated resin (Mercox CL-2B) through the thoracic aorta. Diffuse nodular changes mimicking human cirrhosis were seen in the livers six weeks after injections of DEN. The cirrhotic livers showed an increase of vascular channels composed mainly of venous branches around the regenerating nodules and increased arterioloportal anastonloses. Peribiliary plexi of the cirrhotic livers had more vessels than those of the controls. Many dilated veins and ramificating portal vein branches were also Present. Direct connections between peribiliary plexi and sinusoids or between peribiliary plexi and portal veins were increased in the cirrhotic liver. These results suggest that the peribiliary plexi in experimentally induced cirrhotic liver might play a role in a collateral circulation under a state of portal hypertension.