RRC ID 44848
Author Van Hung T, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Suzuki Y, Hirata K.
Title Inhibition of vascular endothelial growth factor receptor under hypoxia causes severe, human-like pulmonary arterial hypertension in mice: potential roles of interleukin-6 and endothelin.
Journal Life Sci.
Abstract AIMS:Severe pulmonary arterial hypertension (PAH) is an incurable disease whose exact mechanisms remain unknown. However, growing evidence highlights the role of inflammation and endothelin (ET) signaling. The lack of reliable models makes it difficult to investigate the pathophysiology of this disease. Our aim was therefore to develop a mouse model of severe PAH closely mimicking the human condition to explore the role of interleukin-6 (IL-6), and ET signaling in advanced PAH progression.
MAIN METHODS:Young male SV129 mice received vascular endothelial growth factor receptor inhibitor (SU5416) three times a week and were exposed to hypoxia (10% O2) for three weeks. Molecular analysis and histological assessment were examined using real-time PCR, Western blot and immunostaining, respectively.
KEY FINDINGS:The developed murine model presented important characteristics of severe PAH in human: concentric neointimal wall thickening, plexogenic lesions, recruitment of macrophages, and distal arteriolar wall muscularization. We detected an increase of IL-6 production and a stronger macrophage recruitment in adventitia of remodeled arterioles developing plexogenic lesions. Moreover, ET-1 and ET receptor A were up-regulated in lung lysates and media of remodeled arterioles. Recombinant IL-6 stimulated the proliferation and regulated endothelial cells in increasing ET-1 and decreasing ET receptor B.
SIGNIFICANCE:These data describe a murine model, which displays the most important features of human severe PAH. We assume that inflammation, particularly IL-6 regulating ET signaling, plays a crucial role in forming plexogenic lesions. This model is thus reliable and might be used for a better understanding of severe PAH progression and treatment.
Volume 118(2)
Pages 313-28
Published 2014-11-24
DOI 10.1016/j.lfs.2013.12.215
PII S0024-3205(14)00010-1
PMID 24412382
MeSH Animals Biomarkers / metabolism Body Weight / drug effects Cell Hypoxia / drug effects Cell Line Disease Models, Animal Endothelial Cells / drug effects Endothelial Cells / metabolism Endothelial Cells / pathology Endothelin-1 / metabolism* Heart Rate / drug effects Humans Hypertension, Pulmonary / metabolism* Hypertension, Pulmonary / pathology* Hypertension, Pulmonary / physiopathology Indoles / pharmacology Inflammation / pathology Interleukin-6 / metabolism* Lung / blood supply Lung / drug effects Lung / pathology Lung / physiopathology Male Mice Pulmonary Artery / metabolism* Pulmonary Artery / pathology* Pulmonary Artery / physiopathology Pyrroles / pharmacology Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors* Receptors, Vascular Endothelial Growth Factor / metabolism Signal Transduction / drug effects Up-Regulation / drug effects
IF 3.448
Human and Animal Cells