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A Novel Murine Model of Severe Pulmonary Arterial Hypertension

Ciuclan, Loredana and Bonneau, Olivier and Hussey, Martin and Duggan, Nicholas and Holmes, Alan and Good, Robert and Stringer, Rowan and Jones, Peter and Morrell, Nicholas W. and Jarai, Gabor and Walker, Christoph and Westwick, John and Thomas, Matthew (2011) A Novel Murine Model of Severe Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine. ISSN 1073-449X

Abstract

Rationale: The complex pathologies associated with severe pulmonary arterial hypertension (PAH) in man 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 which recapitulates more of the pathologic processes, such as complex vascular remodeling and cardiac indices which 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.
Measurements and Main Results: The combination of VEGFR inhibition with chronic hypoxia profoundly exacerbated all measures of PAH-like pathology when compared to hypoxia alone (>45mmHg right ventricular pressure / >0.35 right ventricular hypertrophy). The changes in pulmonary vascular remodeling in response to hypoxia were further enhanced upon SU5416 treatment. Furthermore, hypoxia/SU5416 treatment steadily decreased cardiac output, indicating incipient heart failure. Molecular analysis showed a dysregulated TGF-β/BMP/Smad axis in SU5416 and/or hypoxia mice as well as augmented induction of IL6 and Hif-1α levels. These changes were observed in accordance with upregulation 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 which correlate with IPAH patient cytokine profiles.
Conclusions: These data describe a novel murine model of PAH which displays many of the hallmarks of the human disease, thus opens new avenues of investigation to better understand PAH pathophysiology.

Item Type: Article
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Keywords: Hypoxia, Sugen, preclinicla mouse model
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/5452

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