Inhibition of VEGFR with SU5416 combined with 3 weeks of chronic hypoxia profoundly exacerbated PAH-like pathology in mice compared with hypoxia alone (> 45 mm Hg right ventricular pressure).
Does VEGFR inhibition with SU5416 combined with chronic hypoxia induce severe pulmonary arterial hypertension pathology in mice compared to hypoxia alone?
The combination of SU5416 and chronic hypoxia establishes a novel murine model that closely mimics severe human pulmonary arterial hypertension.
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.
Ciuclan et al. (Thu,) conducted a other in Severe pulmonary arterial hypertension. SU5416 combined with chronic hypoxia vs. Hypoxia alone was evaluated on PAH pathology development (hemodynamics, cardiac function, histological assessment). Inhibition of VEGFR with SU5416 combined with 3 weeks of chronic hypoxia profoundly exacerbated PAH-like pathology in mice compared with hypoxia alone (> 45 mm Hg right ventricular pressure).