A novel murine model of severe pulmonary arterial hypertension.

Abstract

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 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: 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
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 184 Issue 10 Pg. 1171-82 (Nov 15 2011) ISSN: 1535-4970 [Electronic] United States
• PMID: 21868504 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Indoles
• Pyrroles
• Semaxinib
• Receptors, Vascular Endothelial Growth Factor

Topics

• Acute Disease
• Animals
• Blotting, Western
• Cytokines (blood)
• Disease Models, Animal
• Echocardiography
• Female
• Fluorescent Antibody Technique
• Gene Expression Profiling
• Hemodynamics (drug effects, physiology)
• Hypertension, Pulmonary (etiology, metabolism, pathology, physiopathology)
• Hypoxia (complications)
• Indoles (pharmacology)
• Lung (metabolism, pathology, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Pyrroles (pharmacology)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)