title: Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice.
abstract: Liver vasculature is crucial for adequate hepatic functions. Global deletion of Notch signaling in mice results in liver vascular pathologies. However, whether Notch in endothelium is essential for hepatic vascular structure and function remains unknown. To uncover the function of endothelial Notch in the liver, we deleted Rbpj, a transcription factor mediating all canonical Notch signaling, or Notch1 from the endothelium of postnatal mice. We investigated the hepatic vascular defects in these mutants. The liver was severely affected within 2 weeks of endothelial deletion of Rbpj from birth. Two-week old mutant mice had enlarged vessels on the liver surface, abnormal vascular architecture, and dilated sinusoids. Vascular casting and fluorosphere passage experiments indicated the presence of porto-systemic shunts. These mutant mice presented with severely necrotic liver parenchyma and significantly larger hypoxic areas, likely resulting from vascular shunts. We also found elevated levels of VEGF receptor 3 together with reduced levels of ephrin-B2, suggesting a possible contribution of these factors to the generation of hepatic vascular abnormalities. Deletion of Rbpj from the adult endothelium also led to dilated sinusoids, vascular shunts, and necrosis, albeit milder than that observed in mice with deletion from birth. Similar to deletion of Rbpj, loss of endothelial Notch1 from birth led to similar hepatic vascular malformations within 2 weeks.
  
  
  
  Endothelial Notch signaling is essential for the development and maintenance of proper hepatic vascular architecture and function. These findings may elucidate the molecular pathogenesis of hepatic vascular malformation and the safety of therapeutics inhibiting Notch. (Hepatology 2016;64:1302-1316).
authors.affiliation: Laboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, San Francisco, CA.
authors.forename: Henar
authors.initials: H
authors.lastname: Cuervo
authors.affiliation: Laboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, San Francisco, CA.
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Nielsen
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Simonetto
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA.
authors.forename: Linda
authors.initials: L
authors.lastname: Ferrell
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Vijay H
authors.initials: VH
authors.lastname: Shah
authors.affiliation: Laboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, San Francisco, CA.
authors.forename: Rong A
authors.initials: RA
authors.lastname: Wang
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000502:physiology; D008099:Liver / Q000098:blood supply*; D051379:Mice; D051881:Receptor, Notch1 / Q000502:physiology*; D015398:Signal Transduction; D054079:Vascular Malformations / Q000209:etiology*
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1