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Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development
Author(s) -
Fabris Luca,
Cadamuro Massimiliano,
Libbrecht Louis,
Raynaud Peggy,
Spirlì Carlo,
Fiorotto Romina,
Okolicsanyi Lajos,
Lemaigre Frederic,
Strazzabosco Mario,
Roskams Tania
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22015
Subject(s) - vasculogenesis , biology , angiopoietin , angiogenesis , angiopoietin receptor , mural cell , vascular endothelial growth factor , pathology , microbiology and biotechnology , endocrinology , cancer research , progenitor cell , medicine , stem cell , vascular smooth muscle , smooth muscle , vegf receptors
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. Conclusion: 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. (H EPATOLOGY 2008.)