title: Angiogenesis is crucial for liver regeneration after partial hepatectomy.
abstract: BACKGROUND
  Recent studies of hepatic regeneration have mainly focused on the growth of parenchymal cells. However, remodeling of liver vessels seems to be crucial during hepatic regeneration. In this study, we investigated the influence of antiangiogenesis on hepatic regeneration using sFlt-1, a soluble receptor for vascular endothelial growth factor that acts as a dominant negative receptor, and the hepatocyte growth factor antagonist NK4.
  
  
  METHODS
  A sFlt-1-expressing adenoviral vector, an NK4-expressing adenoviral vector, or both combined were infected into C57BL6 mice via the tail vein. A 70% partial hepatectomy was performed on all of the mice 48 hours after infection. The remnants of the liver were removed after the partial hepatectomy, and hepatic regeneration was assessed by measuring the remnant liver weight and hepatocyte mitosis, bromodeoxyuridine staining, immunohistochemical staining with anti-platelet endothelial cell adhesion molecule-1 antibodies, and real-time polymerase chain reaction studies for angiogenic factors.
  
  
  RESULTS
  The immunohistochemical staining for CD31 showed suppression of sinusoidal endothelial cells growth in sFlt-1-expressing adenoviral vector-and NK4-expressing adenoviral vector-infected mice. Increases in the remnant hepatic weight were significantly lower in the sFlt-1-expressing adenoviral vector-infected mice. The bromodeoxyuridine index and mitotic cell results revealed a significant decrease in hepatic regeneration in the sFlt-1-expressing adenoviral vector-and NK4-expressing adenoviral vector-infected mice. The suppressive effects on hepatic regeneration were significantly enhanced by combined sFlt-1-expressing adenoviral vector and NK4-expressing adenoviral vector infection. Real-time polymerase chain reaction results revealed the significant suppression of angiogenic growth factor receptors Tie-1 and Tie-2.
  
  
  CONCLUSIONS
  The angiogenesis inhibitor significantly suppressed hepatic regeneration. These results suggest that hepatic regeneration after hepatectomy closely correlates with angiogenesis.
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Uda
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Hirano
authors.forename: Gakuhei
authors.initials: G
authors.lastname: Son
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iimuro
authors.forename: Naoki
authors.initials: N
authors.lastname: Uyama
authors.forename: Junichi
authors.initials: J
authors.lastname: Yamanaka
authors.forename: Akira
authors.initials: A
authors.lastname: Mori
authors.forename: Shigeki
authors.initials: S
authors.lastname: Arii
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
mesh_terms: D000256:Adenoviridae; D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000502:physiology; D005822:Genetic Vectors; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D008099:Liver / Q000098:blood supply* / Q000254:growth & development / Q000601:surgery; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D042810:Receptor, TIE-1 / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D015415:Biomarkers; C553307:HGF protein, mouse; D017228:Hepatocyte Growth Factor; C501163:Flt1 protein, mouse; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2; D040281:Vascular Endothelial Growth Factor Receptor-1; C099439:Ang2 protein, mouse; D012259:Ribonuclease, Pancreatic