title: Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome.
abstract: OBJECTIVE
  Hepatopulmonary syndrome (HPS), defined as intrapulmonary vasodilation, occurs in 10%-30% of cirrhotics and increases mortality. In a rat model of HPS induced by common bile duct ligation (CBDL), but not thioacetamide (TAA)-induced nonbiliary cirrhosis, lung capillary density increases, monocytes accumulate in the microvasculature, and signaling factors in the angiogenesis pathway (Akt and endothelial nitric oxide synthase [eNOS]) are activated. Pentoxifylline (PTX) directly decreases lung endothelial Akt and eNOS activation, blocks intravascular monocyte accumulation, and improves experimental HPS; we evaluated whether pulmonary angiogenesis develops in this model.
  
  
  METHODS
  TAA- and PTX-treated animals were evaluated following CBDL. Lung angiogenesis was assessed by quantifying factor VIII-positive microvessels and levels of von Willebrand factor (vWf), vascular endothelial cadherin (VE-cadherin), and proliferating cell nuclear antigen (PCNA). Angiogenic factors including phospho-Akt, phospho-eNOS, vascular endothelial growth factor (VEGF)-A, and phospho-VEGF receptor-2 (p-VEGFR-2) were compared and monocyte accumulation was assessed.
  
  
  RESULTS
  Following CBDL, but not TAA exposure, rats developed HPS that was temporally correlated with increased numbers of lung microvessel; increased levels of vWf, VE-cadherin and PCNA; and activation of Akt and eNOS. Angiogenesis was accompanied by increased pulmonary VEGF-A and p-VEGFR-2 levels, with VEGF-A staining in accumulated intravascular monocytes and alveolar endothelial cells. Following CBDL, PTX-treated rats had reduced numbers of microvessels, reduced lung monocyte accumulation, downregulation of pulmonary angiogenic factors, and reduced symptoms of HPS.
  
  
  CONCLUSIONS
  A specific increase in pulmonary angiogenesis occurs as experimental HPS develops, accompanied by activation of VEGF-A-associated angiogenic pathways. PTX decreases the angiogenesis, reduces the symptoms of HPS, and downregulates VEGF-A mediated pathways.
authors.affiliation: Department of Internal Medicine and Liver Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhang
authors.forename: Bao
authors.initials: B
authors.lastname: Luo
authors.forename: Liping
authors.initials: L
authors.lastname: Tang
authors.forename: Yongming
authors.initials: Y
authors.lastname: Wang
authors.forename: Cecil R
authors.initials: CR
authors.lastname: Stockard
authors.forename: Inga
authors.initials: I
authors.lastname: Kadish
authors.forename: Thomas
authors.initials: T
authors.lastname: Van Groen
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Selvarangan
authors.initials: S
authors.lastname: Ponnazhagan
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fallon
mesh_terms: D043168:Angiostatins / Q000494:pharmacology; D000818:Animals; D003135:Common Bile Duct; D004195:Disease Models, Animal; D043169:Endostatins / Q000494:pharmacology; D020065:Hepatopulmonary Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D008026:Ligation; D008297:Male; D008833:Microcirculation / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011652:Pulmonary Circulation / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013853:Thioacetamide / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D043169:Endostatins; D018809:Proliferating Cell Nuclear Antigen; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; C467498:vascular endothelial growth factor A, rat; D013853:Thioacetamide; D043168:Angiostatins; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D010431:Pentoxifylline