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Increased Lymphangiogenesis in Animal Models of Pulmonary Arterial Hypertension
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A3759 - Increased Lymphangiogenesis in Animal Models of Pulmonary Arterial Hypertension
Author Block: P. Zhang1, A. W. Tian2, A. B. Tu3, X. Jiang4, M. R. Nicolls5; 1Depart of Pulmonary and Critical Care, Stanford School of Medicine, Palo Alto, CA, United States, 2Stanford University, Redwood City, CA, United States, 3Stanford School of Medicine, Fremont, CA, United States, 4Stanford Univ, Palo Alto, CA, United States, 5Stanford School of Medicine, Palo Alto, CA, United States.
Title:
Authors: Patrick Zhang, Amy Tian, Allen Tu, Xinguo Jiang and Mark Nicolls
Institution: Department of Pulmonary and Critical Care, School of Medicine, Stanford University
Rational:
The lymphatic system is essential for the maintenance of tissue fluid homeostasis, gastrointestinal lipid absorption, and immune trafficking. There is mounting evidence of a role for the lymphatic circulation and lymphangiogenesis in the pathogenesis of many pulmonary dysfunctions, including idiopathic pulmonary fibrosis and lung transplantation rejection. However, the involvement of lymphangiogenesis in pulmonary arterial hypertension (PAH) has not been investigated. We recently reported that Leukotriene B4 (LTB4) prevents the lymphatic repair by blocking the key lymphangiogenic signaling, VEGFR3 and Notch signaling, and causes lymphedema exacerbation. LTB4 induces PAH in many animal models of PAH. A clinical trial testing the efficacy LTB4 antagonism in this disease is under way. However, whether LTB4 signaling impacts lymphatic vessel in the lung and whether such regulation affects the vascular remodeling in pulmonary arterial hypertension is undetermined.
Methods:
Lung sections were taken from three different animal models of PAH including chronic hypoxia mouse model, BMPR2 heterozygous rat model, and monocrotaline rat model. Lymphatics were visualized in the reporter mice under confocal microscopy with red fluorescence tied to the expression of the lymphatic marker Prox1 (Prox1-Cre-ERT2-tdTomato mice). Whereas, the lymphatic network in the lung tissues from the rat study were immunofluorescence stained with three lymphatic markers: Lyve-1, VEGFR3, and Podoplanin. Western blot and quantitative PCR was performed to assess the expression levels of total and phosphorylated VEGFR3, LYVE-1 and Notch.
Results:
Tomato fluorescence-labeled lymphatics were increased in mice subjected to hypoxia chamber. Immunofluorescence staining suggested a rise of Lyve-1 and VEGFR3 signal in both rat models of PAH compared to controls. Western blots and PCR investigating the protein and mRNA expression of VEGFR3, LYVE-1 and Notch correlated with the staining results. Blocking LTB4in the BMPR2 heterozygous rat model and monocrotaline rat model of PAH reduced lymphangiogenesis.
Conclusion:
Increased lymphangiogenesis was observed in the lung samples of animals with PAH. Blocking LTB4 reduced the growth of new lymphatic vessels. Future study will focus on illustrating the molecular and cellular mechanism of LTB4-regulated lymphangiogenesis in PAH.
Funding: R01 HL138473
Author Block: P. Zhang1, A. W. Tian2, A. B. Tu3, X. Jiang4, M. R. Nicolls5; 1Depart of Pulmonary and Critical Care, Stanford School of Medicine, Palo Alto, CA, United States, 2Stanford University, Redwood City, CA, United States, 3Stanford School of Medicine, Fremont, CA, United States, 4Stanford Univ, Palo Alto, CA, United States, 5Stanford School of Medicine, Palo Alto, CA, United States.
Title:
Authors: Patrick Zhang, Amy Tian, Allen Tu, Xinguo Jiang and Mark Nicolls
Institution: Department of Pulmonary and Critical Care, School of Medicine, Stanford University
Rational:
The lymphatic system is essential for the maintenance of tissue fluid homeostasis, gastrointestinal lipid absorption, and immune trafficking. There is mounting evidence of a role for the lymphatic circulation and lymphangiogenesis in the pathogenesis of many pulmonary dysfunctions, including idiopathic pulmonary fibrosis and lung transplantation rejection. However, the involvement of lymphangiogenesis in pulmonary arterial hypertension (PAH) has not been investigated. We recently reported that Leukotriene B4 (LTB4) prevents the lymphatic repair by blocking the key lymphangiogenic signaling, VEGFR3 and Notch signaling, and causes lymphedema exacerbation. LTB4 induces PAH in many animal models of PAH. A clinical trial testing the efficacy LTB4 antagonism in this disease is under way. However, whether LTB4 signaling impacts lymphatic vessel in the lung and whether such regulation affects the vascular remodeling in pulmonary arterial hypertension is undetermined.
Methods:
Lung sections were taken from three different animal models of PAH including chronic hypoxia mouse model, BMPR2 heterozygous rat model, and monocrotaline rat model. Lymphatics were visualized in the reporter mice under confocal microscopy with red fluorescence tied to the expression of the lymphatic marker Prox1 (Prox1-Cre-ERT2-tdTomato mice). Whereas, the lymphatic network in the lung tissues from the rat study were immunofluorescence stained with three lymphatic markers: Lyve-1, VEGFR3, and Podoplanin. Western blot and quantitative PCR was performed to assess the expression levels of total and phosphorylated VEGFR3, LYVE-1 and Notch.
Results:
Tomato fluorescence-labeled lymphatics were increased in mice subjected to hypoxia chamber. Immunofluorescence staining suggested a rise of Lyve-1 and VEGFR3 signal in both rat models of PAH compared to controls. Western blots and PCR investigating the protein and mRNA expression of VEGFR3, LYVE-1 and Notch correlated with the staining results. Blocking LTB4in the BMPR2 heterozygous rat model and monocrotaline rat model of PAH reduced lymphangiogenesis.
Conclusion:
Increased lymphangiogenesis was observed in the lung samples of animals with PAH. Blocking LTB4 reduced the growth of new lymphatic vessels. Future study will focus on illustrating the molecular and cellular mechanism of LTB4-regulated lymphangiogenesis in PAH.
Funding: R01 HL138473
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