title: A novel murine model of severe pulmonary arterial hypertension.
abstract: BACKGROUND
  The complex pathologies associated with severe pulmonary arterial hypertension (PAH) in humans have been a challenge to reproduce in mice due to the subtle phenotype displayed to PAH stimuli.
  
  
  OBJECTIVE
  Here we aim to develop a novel murine model of PAH that recapitulates more of the pathologic processes, such as complex vascular remodeling and cardiac indices, that are not characteristic of alternative mouse models.
  
  
  METHODS
  Inhibition of vascular endothelial growth factor receptor (VEGFR) with SU5416 combined with 3 weeks of chronic hypoxia was investigated. Hemodynamics, cardiac function, histological assessment of pulmonary vasculature, and molecular pathway analysis gauged the extent of PAH pathology development.
  
  
  RESULTS
  The combination of VEGFR inhibition with chronic hypoxia profoundly exacerbated all measures of PAH-like pathology when compared with hypoxia alone (> 45 mm Hg right ventricular pressure, > 0.35 right ventricular hypertrophy). The changes in pulmonary vascular remodeling in response to hypoxia were further enhanced on SU5416 treatment. Furthermore, hypoxia/SU5416 treatment steadily decreased cardiac output, indicating incipient heart failure. Molecular analysis showed a dysregulated transforming growth factor-β/bone morphogenetic protein/Smad axis in SU5416- and/or hypoxia-treated mice as well as augmented induction of IL-6 and Hif-1α levels. These changes were observed in accordance with up-regulation of Tph1 and Pdgfr gene transcripts as well as a rise in platelet-rich serotonin. Biomarker analysis in response to VEGFR inhibition and/or hypoxia revealed distinct signatures that correlate with cytokine profiles of patients with idiopathic PAH.
  
  
  CONCLUSIONS
  These data describe a novel murine model of PAH, which displays many of the hallmarks of the human disease, thus opening new avenues of investigation to better understand PAH pathophysiology.
authors.affiliation: Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham, West Sussex, UK.
authors.forename: Loredana
authors.initials: L
authors.lastname: Ciuclan
authors.forename: Olivier
authors.initials: O
authors.lastname: Bonneau
authors.forename: Martin
authors.initials: M
authors.lastname: Hussey
authors.forename: Nicholas
authors.initials: N
authors.lastname: Duggan
authors.forename: Alan M
authors.initials: AM
authors.lastname: Holmes
authors.forename: Robert
authors.initials: R
authors.lastname: Good
authors.forename: Rowan
authors.initials: R
authors.lastname: Stringer
authors.forename: Peter
authors.initials: P
authors.lastname: Jones
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Gabor
authors.initials: G
authors.lastname: Jarai
authors.forename: Christoph
authors.initials: C
authors.lastname: Walker
authors.forename: John
authors.initials: J
authors.lastname: Westwick
authors.forename: Matthew
authors.initials: M
authors.lastname: Thomas
mesh_terms: D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications; D007211:Indoles / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011758:Pyrroles / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors
chemical_list: D016207:Cytokines; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D040262:Receptors, Vascular Endothelial Growth Factor