Pulmonary Angiogenesis in a Rat Model of Hepatopulmonary Syndrome

Junlan Zhang, Bao Luo, Liping Tang, Yongming Wang, Cecil R. Stockard, Inga Kadish, Thomas Van Groen, William E. Grizzle, Selvarangan Ponnazhagan, Michael B. Fallon

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1070-1080
Number of pages11
JournalGastroenterology
Volume136
Issue number3
DOIs
StatePublished - Mar 2009
Externally publishedYes

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Hepatopulmonary Syndrome
Lung
Pentoxifylline
Vascular Endothelial Growth Factor A
Nitric Oxide Synthase Type III
Common Bile Duct
Monocytes
Thioacetamide
Microvessels
Ligation
Angiogenesis Inducing Agents
Proliferating Cell Nuclear Antigen
von Willebrand Factor
Down-Regulation
Alveolar Epithelial Cells
Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor Receptor
Factor VIII
Vasodilation
Fibrosis

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Zhang, J., Luo, B., Tang, L., Wang, Y., Stockard, C. R., Kadish, I., ... Fallon, M. B. (2009). Pulmonary Angiogenesis in a Rat Model of Hepatopulmonary Syndrome. Gastroenterology, 136(3), 1070-1080. https://doi.org/10.1053/j.gastro.2008.12.001

Pulmonary Angiogenesis in a Rat Model of Hepatopulmonary Syndrome. / Zhang, Junlan; Luo, Bao; Tang, Liping; Wang, Yongming; Stockard, Cecil R.; Kadish, Inga; Van Groen, Thomas; Grizzle, William E.; Ponnazhagan, Selvarangan; Fallon, Michael B.

In: Gastroenterology, Vol. 136, No. 3, 03.2009, p. 1070-1080.

Research output: Contribution to journalArticle

Zhang, J, Luo, B, Tang, L, Wang, Y, Stockard, CR, Kadish, I, Van Groen, T, Grizzle, WE, Ponnazhagan, S & Fallon, MB 2009, 'Pulmonary Angiogenesis in a Rat Model of Hepatopulmonary Syndrome', Gastroenterology, vol. 136, no. 3, pp. 1070-1080. https://doi.org/10.1053/j.gastro.2008.12.001
Zhang J, Luo B, Tang L, Wang Y, Stockard CR, Kadish I et al. Pulmonary Angiogenesis in a Rat Model of Hepatopulmonary Syndrome. Gastroenterology. 2009 Mar;136(3):1070-1080. https://doi.org/10.1053/j.gastro.2008.12.001
Zhang, Junlan ; Luo, Bao ; Tang, Liping ; Wang, Yongming ; Stockard, Cecil R. ; Kadish, Inga ; Van Groen, Thomas ; Grizzle, William E. ; Ponnazhagan, Selvarangan ; Fallon, Michael B. / Pulmonary Angiogenesis in a Rat Model of Hepatopulmonary Syndrome. In: Gastroenterology. 2009 ; Vol. 136, No. 3. pp. 1070-1080.
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AU - Luo, Bao

AU - Tang, Liping

AU - Wang, Yongming

AU - Stockard, Cecil R.

AU - Kadish, Inga

AU - Van Groen, Thomas

AU - Grizzle, William E.

AU - Ponnazhagan, Selvarangan

AU - Fallon, Michael B.

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N2 - 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.

AB - 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.

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