title: Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases.
abstract: Liver involvement in autosomal dominant polycystic kidney disease (ADPKD) is characterized by altered remodeling of the embryonic ductal plate (DP) with presence of biliary cysts and aberrant portal vasculature. The genetic defect causing ADPKD has been identified, but mechanisms of liver cyst growth remain uncertain. To investigate the possible role of angiogenic mechanisms, we have studied the immunohistochemical expression of vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and their receptors (VEGFR-1, VEGFR-2, Tie-2) in ADPKD, Caroli's disease, normal and fetal livers. In ADPKD and control livers Ang-1 and Ang-2 gene expression was studied by real-time-PCR. Effects of VEGF on cholangiocyte proliferation were studied by PCNA Western Blot in isolated rat cholangiocytes and by MTS assay in cultured cholangiocytes isolated from ADPKD patients and from an ADPKD mouse model (Pkd2(WS25/-)). Cholangiocytes were strongly positive for VEGF, VEGFR-1, VEGFR-2 and Ang-2 in ADPKD and Caroli, and also for Ang-1 and Tie-2 in ADPKD, similar to fetal ductal plate cells. VEGF stimulated proliferation in both normal and ADPKD cholangiocytes, but the effect was particularly evident in the latter. Ang-1 alone had no effect, but was synergic to VEGF. VEGF expression on cholangiocytes positively correlated with microvascular density. In conclusion, consistent with the immature phenotype of the cystic epithelium, expression of VEGF, VEGFRs, Ang-1 and Tie-2 is strongly upregulated in cholangiocytes from polycystic liver diseases. VEGF and Ang-1 have autocrine proliferative effect on cholangiocyte growth and paracrine effect on portal vasculature, thus promoting the growth of the cysts and their vascular supply. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
authors.affiliation: Center for Liver Research, Gastroenterology Division, Ospedali Riuniti, Bergamo, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Fabris
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cadamuro
authors.forename: Romina
authors.initials: R
authors.lastname: Fiorotto
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.forename: Carlo
authors.initials: C
authors.lastname: Spirlì
authors.forename: Saida
authors.initials: S
authors.lastname: Melero
authors.forename: Aurelio
authors.initials: A
authors.lastname: Sonzogni
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Joplin
authors.forename: Lajos
authors.initials: L
authors.lastname: Okolicsanyi
authors.forename: Mario
authors.initials: M
authors.lastname: Strazzabosco
mesh_terms: D042501:Angiogenic Proteins / Q000096:biosynthesis*; D000818:Animals; D001652:Bile Ducts / Q000166:cytology* / Q000378:metabolism*; D003560:Cysts / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D042501:Angiogenic Proteins; D042461:Vascular Endothelial Growth Factor A