title: Ischemia reperfusion of the hepatic artery induces the functional damage of large bile ducts by changes in the expression of angiogenic factors.
abstract: Liver transplantation and cholangiocarcinoma induce biliary dysfunction following ischemia reperfusion (IR). The function of the intrahepatic biliary tree is regulated by both autocrine and paracrine factors. The aim of the study was to demonstrate that IR-induced damage of cholangiocytes is associated with altered expression of biliary angiogenic factors. Normal and bile duct ligation rats underwent 24-h sham or hepatic reperfusion after 30 min of transient occlusion of the hepatic artery (HAIR) or portal vein (PVIR) before collecting liver blocks and cholangiocyte RNA or protein. We evaluated liver histology, biliary apoptosis, proliferation and expression of VEGF-A/C, VEGFR-2/3, Ang-1/2, and Tie-1/2 in liver sections and isolated small and large cholangiocytes. Normal rat intrahepatic cholangiocyte cultures (NRICC) were maintained under standard conditions in normoxic or under a hypoxic atmosphere for 4 h and then transferred to normal conditions for selected times. Subsequently, we measured changes in biliary proliferation and apoptosis and the expression of VEGF-A/C and VEGFR-2/3. In vivo, HAIR (but not PVIR) induced damage of large bile ducts and decreased proliferation and secretin-stimulated cAMP levels. HAIR-induced damage of large bile ducts was associated with increased expression of VEGF-A/C, VEGFR-2/3, Ang-1/2, and Tie-1/2. In vitro, under hypoxic conditions, there was increased apoptosis and reduced proliferation of NRICC concomitant with enhanced expression of VEGF-A/C and VEGFR-2/3. The functional damage of large bile ducts by HAIR and hypoxia is associated with increased expression of angiogenic factors in small cholangiocytes, presumably due to a compensatory mechanism in response to biliary damage.
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
authors.forename: Romina
authors.initials: R
authors.lastname: Mancinelli
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, Texas; Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, Texas; Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
authors.forename: Guido
authors.initials: G
authors.lastname: Carpino
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy; Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Franchitto
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy;
authors.forename: Antonella
authors.initials: A
authors.lastname: Vetuschi
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Sferra
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
authors.forename: Luigi
authors.initials: L
authors.lastname: Pannarale
authors.affiliation: Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, Texas; Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, Texas; Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy; paolo.onori@uniroma1.it.
authors.forename: Paolo
authors.identifier: http://orcid.org/0000-0002-7195-3760
authors.initials: P
authors.lastname: Onori
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D002779:Cholestasis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D006499:Hepatic Artery / Q000503:physiopathology / Q000601:surgery*; D008102:Liver Circulation; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012633:Secretin / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D042501:Angiogenic Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C467498:vascular endothelial growth factor A, rat; D012633:Secretin; D000242:Cyclic AMP; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: angiogenic factors; biliary tree; cholangiocytes; liver; transplantation