title: Liver regeneration is an angiogenesis- associated phenomenon.
abstract: OBJECTIVE
  To investigate whether liver regeneration is an angiogenesis-associated phenomenon.
  
  
  BACKGROUND
  Angiogenesis is predominantly known for its pivotal role in tumor growth. However, angiogenesis could also play a role in physiologic processes involving tissue repair, such as liver regeneration.
  
  
  METHODS
  Mice subjected to 70% partial hepatectomy were treated with human angiostatin (100 mg/kg body weight). Regeneration-induced hepatic angiogenesis was determined by assessing intrahepatic microvascular density using CD31 staining of frozen liver sections. Liver regeneration was evaluated by assessing wet liver weights and BrdU incorporation in DNA at regular intervals after partial hepatectomy. Possible direct effects of angiostatin on hepatocytes were studied by assessment of liver enzymes (ASAT, ALAT, bilirubin, lactate dehydrogenase), MTT assay (cytotoxicity), aminophenol production (metabolic function), and TUNEL (apoptosis).
  
  
  RESULTS
  In a regenerating liver, microvascular density increased by 38%. Angiostatin significantly inhibited this response by 60%. In addition, angiostatin inhibited liver regeneration by 50.4% and 24.9% on postoperative days 7 and 14, respectively. In control mice liver weights regained normalcy in 8 days, whereas those in angiostatin-treated mice normalized after 21 days. In angiostatin-treated mice, the maximal BrdU incorporation was decreased and delayed. Direct adverse effects of angiostatin on cultured and in vivo hepatocytes were not observed. Angiostatin neither induced necrosis on hematoxylin and eosin staining nor affected serum levels of liver enzymes.
  
  
  CONCLUSIONS
  Liver regeneration is accompanied by intrahepatic angiogenesis. Antiangiogenic treatment using angiostatin inhibits both phenomena. The authors conclude that liver regeneration is, at least in part, an angiogenesis-dependent phenomenon.
authors.affiliation: Department of Surgery, University Medical Center, Utrecht, The Netherlands.
authors.forename: Tom A
authors.initials: TA
authors.lastname: Drixler
authors.forename: Mathys J
authors.initials: MJ
authors.lastname: Vogten
authors.forename: Ewan D
authors.initials: ED
authors.lastname: Ritchie
authors.forename: Theo J M V
authors.initials: TJ
authors.lastname: van Vroonhoven
authors.forename: Martijn F B G
authors.initials: MF
authors.lastname: Gebbink
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
authors.forename: Inne H M
authors.initials: IH
authors.lastname: Borel Rinkes
mesh_terms: D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D043168:Angiostatins; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000473:pathology*; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010958:Plasminogen / Q000494:pharmacology*; D011336:Probability; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity
chemical_list: D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen