A Novel Murine Model of Severe Pulmonary Arterial Hypertension

作者：Ciuclan Loredana; Bonneau Olivier; Hussey Martin; Duggan Nicholas; Holmes Alan M; Good Robert; Stringer Rowan; Jones Peter; Morrell Nicholas W; Jarai Gabor; Walker Christoph; Westwick John; Thomas Matthew^*

来源：American Journal of Respiratory and Critical Care Medicine, 2011, 184(10): 1171-1182.

DOI：10.1164/rccm.201103-0412OC

• pulmonary arterial hypertension
• animal preclinical models
• hypoxia
• vascular endothelial growth factor receptor

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-beta/bone morphogenetic protein/Smad axis in SU5416-and/or hypoxia-treated mice as well as augmented induction of IL-6 and Hif-1 alpha 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.

• 出版日期2011-11-15