title: Inhibition of vascular endothelial growth factor receptor under hypoxia causes severe, human-like pulmonary arterial hypertension in mice: potential roles of interleukin-6 and endothelin.
abstract: OBJECTIVE
  Severe pulmonary arterial hypertension (PAH) is an incurable disease whose exact mechanisms remain unknown. However, growing evidence highlights the role of inflammation and endothelin (ET) signaling. The lack of reliable models makes it difficult to investigate the pathophysiology of this disease. Our aim was therefore to develop a mouse model of severe PAH closely mimicking the human condition to explore the role of interleukin-6 (IL-6), and ET signaling in advanced PAH progression.
  
  
  METHODS
  Young male SV129 mice received vascular endothelial growth factor receptor inhibitor (SU5416) three times a week and were exposed to hypoxia (10% O2) for three weeks. Molecular analysis and histological assessment were examined using real-time PCR, Western blot and immunostaining, respectively.
  
  
  RESULTS
  The developed murine model presented important characteristics of severe PAH in human: concentric neointimal wall thickening, plexogenic lesions, recruitment of macrophages, and distal arteriolar wall muscularization. We detected an increase of IL-6 production and a stronger macrophage recruitment in adventitia of remodeled arterioles developing plexogenic lesions. Moreover, ET-1 and ET receptor A were up-regulated in lung lysates and media of remodeled arterioles. Recombinant IL-6 stimulated the proliferation and regulated endothelial cells in increasing ET-1 and decreasing ET receptor B.
  
  
  CONCLUSIONS
  These data describe a murine model, which displays the most important features of human severe PAH. We assume that inflammation, particularly IL-6 regulating ET signaling, plays a crucial role in forming plexogenic lesions. This model is thus reliable and might be used for a better understanding of severe PAH progression and treatment.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicie, Kobe, Japan.
authors.forename: Tran
authors.initials: T
authors.lastname: Van Hung
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicie, Kobe, Japan; Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan. Electronic address: emoto@med.kobe-u.ac.jp.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Emoto
authors.affiliation: Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vignon-Zellweger
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicie, Kobe, Japan; Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yagi
authors.affiliation: Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicie, Kobe, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hirata
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019332:Endothelin-1 / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D011758:Pyrroles / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D019332:Endothelin-1; D007211:Indoles; D015850:Interleukin-6; D011758:Pyrroles; C116890:Semaxinib; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Endothelin-1; Interleukin-6; Macrophage; Pulmonary arterial hypertension