A Novel Murine Model of Severe Pulmonary Arterial Hypertension

作者：Loredana I. Ciuclan, Olivier Bonneau, Martin J. Hussey, Nicholas Duggan, Alan M. Holmes, Robert B. Good, Rowan A. Stringer, Peter Lloyd Jones, Nicholas W. Morrell, Gábor Járai, Christoph Walker, John K. Westwick, Matthew James Thomas · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2011 · DOI：10.1164/rccm.201103-0412oc · 被引用次数：251 · 研究领域：Pulmonary Hypertension Research and Treatments、Nitric Oxide and Endothelin Effects、Cardiac Fibrosis and Remodeling

RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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...