title: Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development.
abstract: Intrahepatic bile ducts maintain a close anatomical relationship with hepatic arteries. During liver ontogenesis, the development of the hepatic artery appears to be modulated by unknown signals originating from the bile duct. Given the capability of cholangiocytes to produce angiogenic growth factors and influence peribiliary vascularization, we studied the immunohistochemical expression of vascular endothelial growth factor (VEGF), angiopoietin-1, angiopoietin-2, and their cognate receptors (VEGFR-1, VEGFR-2, Tie-2) in fetal human livers at different gestational ages and in mice characterized by defective biliary morphogenesis (Hnf6(-/-)). The results showed that throughout the different developmental stages, VEGF was expressed by developing bile ducts and angiopoietin-1 by hepatoblasts, whereas their cognate receptors were variably expressed by vascular cells according to the different maturational stages. Precursors of endothelial and mural cells expressed VEGFR-2 and Tie-2, respectively. In immature hepatic arteries, endothelial cells expressed VEGFR-1, whereas mural cells expressed both Tie-2 and Angiopoietin-2. In mature hepatic arteries, endothelial cells expressed Tie-2 along with VEGFR-1. In early postnatal Hnf6(-/-) mice, VEGF-expressing ductal plates failed to incorporate into the portal mesenchyma, resulting in severely altered arterial vasculogenesis.
  
  
  CONCLUSIONS
  The reciprocal expression of angiogenic growth factors and receptors during development supports their involvement in the cross talk between liver epithelial cells and the portal vasculature. Cholangiocytes generate a VEGF gradient that is crucial during the migratory stage, when it determines arterial vasculogenesis in their vicinity, whereas angiopoietin-1 signaling from hepatoblasts contributes to the remodeling of the hepatic artery necessary to meet the demands of the developing epithelium.
authors.affiliation: CeLiveR, Center for Liver Research, Ospedali Riuniti di Bergamo, Bergamo, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Fabris
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cadamuro
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.forename: Peggy
authors.initials: P
authors.lastname: Raynaud
authors.forename: Carlo
authors.initials: C
authors.lastname: Spirlì
authors.forename: Romina
authors.initials: R
authors.lastname: Fiorotto
authors.forename: Lajos
authors.initials: L
authors.lastname: Okolicsanyi
authors.forename: Frederic
authors.initials: F
authors.lastname: Lemaigre
authors.forename: Mario
authors.initials: M
authors.lastname: Strazzabosco
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000196:embryology; D004847:Epithelial Cells / Q000502:physiology*; D005865:Gestational Age; D006133:Growth Substances / Q000502:physiology*; D006499:Hepatic Artery / Q000166:cytology* / Q000502:physiology*; D051559:Hepatocyte Nuclear Factor 6 / Q000172:deficiency; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D011168:Portal System / Q000196:embryology / Q000473:pathology / Q000502:physiology
chemical_list: D006133:Growth Substances; D051559:Hepatocyte Nuclear Factor 6; C496606:Onecut1 protein, mouse