A Novel Murine Model of Severe Pulmonary Arterial Hypertension

• DOI: 10.1164/rccm.201103-0412oc
• Publication Date: 2011-08-26T02:06:52Z
• Authors: Loredana Ciuclan; Olivier Bonneau; Martin Hussey; Nicholas Duggan; Alan M. Holmes; Robert Good; Rowan Stringer; Peter Jones; Nicholas W. Morrell; Gabor Jarai; Christoph Walker; John Westwick; Matthew Thomas
• Keywords: Hypoxia; BMPR2; Pulmonary pathology; Right ventricular hypertrophy; Hypoxia-Inducible Factors

The complex pathologies associated with severe pulmonary arterial hypertension (PAH) in humans have been a challenge to reproduce mice due the subtle phenotype displayed PAH stimuli.Here we aim develop novel murine model of that recapitulates more pathologic processes, such as vascular remodeling and cardiac indices, are not characteristic alternative mouse models.Inhibition endothelial growth factor receptor (VEGFR) SU5416 combined 3 weeks chronic hypoxia was investigated. Hemodynamics, function, histological assessment vasculature, molecular pathway analysis gauged extent pathology development.The combination VEGFR inhibition profoundly exacerbated all measures PAH-like when compared alone (> 45 mm Hg right ventricular pressure, > 0.35 hypertrophy). changes response were further enhanced on treatment. Furthermore, hypoxia/SU5416 treatment steadily decreased output, indicating incipient heart failure. Molecular showed dysregulated transforming factor-β/bone morphogenetic protein/Smad axis SU5416- and/or hypoxia-treated well augmented induction IL-6 Hif-1α levels. These observed accordance up-regulation Tph1 Pdgfr gene transcripts rise platelet-rich serotonin. Biomarker revealed distinct signatures correlate cytokine profiles patients idiopathic PAH.These data describe PAH, which displays many hallmarks human disease, thus opening new avenues investigation better understand pathophysiology.