Journal
PLOS ONE
Volume 10, Issue 7, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0129489
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Funding
- Foundation of Anesthesia Education and Research (FAER)
- American Heart Association
- Flight Attendants Medical Research Institute (FAMRI)
- National Heart Lung and Blood Institute of the National Institutes of Health [R01 HL056470, HL088029]
- European Regional Development Fund-Project FNUSA-ICRC [CZ.1.05/1.1.00/02.0123]
- ICRC Human Bridge - Support of Study Stays of Czech Researchers Abroad: Young Talent Incubator - European Social Fund [CZ.1.07/2.3.00/20.0022]
- state budget of the Czech Republic
- National Science Foundation [B-179-M]
- Mayo Clinic Center for Translational Science
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Background Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs). Methods and Results 48h of 1% hypoxia enhanced BDNF and TrkB expression, as well as release of BDNF. In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline. In isolated PASMCs, hypoxia-induced BDNF increased intracellular Ca2+ responses to serotonin: an effect altered by HIF1 alpha inhibition or by neutralization of extracellular BDNF via chimeric TrkB-Fc. Enhanced BDNF/TrkB signaling increased PASMC survival and proliferation, and decreased apoptosis following hypoxia. Conclusions Enhanced expression and signaling of the BDNF-TrkB system in PASMCs is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function. Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy.
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