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Eugenio Gaudio1, Antonio Franchitto2, Luigi Pannarale, Guido Carpino3, Gianfranco Alpini4, Heather Francis5, Shannon Glaser6, Domenico Alvaro7, Paolo Onori 81Eugenio Gaudio, Antonio Franchitto, Luigi Pannarale, Guido Carpino, Department of Human Anatomy, University of Rome “La Sapienza”, Rome, Italy 4Gianfranco Alpini, Central Texas Veterans Health Care System, and Department of Medicine and Systems Biology and Translational Medicine, College of Medicine, Temple, TX, United States 5Heather Francis, Division of Research and Education, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, TX, United States 6Shannon Glaser, Department of Medicine and Division of Research and Education, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, TX, United States 7Domenico Alvaro, Division of Gastroenterology, University of Rome “La Sapienza”, Rome, Italy; University of Rome “La Sapienza”, Polo Pontino, Latina, Italy 8Paolo Onori, Department of Experimental Medicine, Section of Human and Clinical Anatomy, State University of L'Aquila, L'Aquila, Italy
Supported by MIUR grants PRIN 2005 (prot. 2005067975_001) to E. Gaudio and Biomedicina, Cluster C04, Progetto n. 5 to E.Gaudio-P.Onori; MIUR grants PRIN 2005 (prot.No: 2005067975_002) to D. Alvaro and a VA Research Scholar Award, a VA Merit Award and the NIH grants DK58411 and DK062975 to Gianfranco Alpini
Correspondence to: Eugenio Gaudio, MD, University of Rome, "La Sapienza", Department of Human Anatomy, Rome, Italy. [email protected]
Telephone: +39-06-49918055 Fax: +39-06-49918062 Abstract
The microvascular supply of the biliary tree, the peribiliary plexus (PBP), stems from the hepatic artery branches and flows into the hepatic sinusoids. A detailed three-dimensional study of the PBP has been performed by using the Scanning Electron Microscopy vascular corrosion casts (SEMvcc) technique. Considering that the PBP plays a fundamental role in supporting the secretory and absorptive functions of the biliary epithelium, their organization in either normalcy and pathology is explored. The normal liver shows the PBP arranged around extra- and intrahepatic biliary tree. In the small portal tract PBP was characterized by a single layer of capillaries which progressively continued with the extrahepatic PBP where it showed a more complex vascular network. After common duct ligation (BDL), progressive modifications of bile duct and PBP proliferation are observed. The PBP presents a three-dimensional network arranged around many bile ducts and appears as bundles of vessels, composed by capillaries of homogeneous diameter with a typical round mesh structure. The PBP network is easily distinguishable from the sinusoidal network which appears normal. Considering the enormous extension of the PBP during BDL, the possible role played by the Vascular Endothelial Growth Factor (VEGF) is evaluated. VEGF-A, VEGF-C and their related receptors appeared highly immunopositive in proliferating cholangiocytes of BDL rats. The administration of anti-VEGF-A or anti-VEGF-C antibodies to BDL rats as well as hepatic artery ligation induced a reduced bile duct mass. The administration of rVEGF-A to BDL hepatic artery ligated rats prevented the decrease of cholangiocyte proliferation and VEGF-A expression as compared to BDL control rats. These data suggest the role of arterial blood supply of the biliary tree in conditions of cholangiocyte proliferation, such as it occurs during chronic cholestasis. On the other hand, the role played by VEGF as a tool of cross-talk between cholangiocytes and PBP endothelial cells suggests that manipulation of VEGF release and function could represent a therapeutic strategy for human pathological conditions characterized by damage of hepatic artery or the biliary tree. Key words: Peribiliary plexus; Periportal plexus; Cholangiocytes
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