Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome

Gastroenterology. 2009 Mar;136(3):1070-80. doi: 10.1053/j.gastro.2008.12.001. Epub 2008 Dec 3.


Background & aims: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiostatins / pharmacology
  • Animals
  • Common Bile Duct
  • Disease Models, Animal
  • Endostatins / pharmacology
  • Hepatopulmonary Syndrome / chemically induced
  • Hepatopulmonary Syndrome / drug therapy
  • Hepatopulmonary Syndrome / physiopathology*
  • Ligation
  • Male
  • Microcirculation / physiology
  • Neovascularization, Pathologic / chemically induced
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / physiopathology*
  • Nitric Oxide Synthase Type III / metabolism
  • Pentoxifylline / pharmacology
  • Proliferating Cell Nuclear Antigen / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pulmonary Circulation / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology
  • Thioacetamide / pharmacology
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Vasodilator Agents / pharmacology


  • Endostatins
  • Proliferating Cell Nuclear Antigen
  • Vascular Endothelial Growth Factor A
  • Vasodilator Agents
  • vascular endothelial growth factor A, rat
  • Thioacetamide
  • Angiostatins
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Vascular Endothelial Growth Factor Receptor-2
  • Proto-Oncogene Proteins c-akt
  • Pentoxifylline