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 HIF1α 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.

Department of Anesthesiology Mayo Clinic Rochester Minnesota 55905 United States of America

Department of Anesthesiology Mayo Clinic Rochester Minnesota 55905 United States of America; Department of Physiology and Biomedical Engineering Mayo Clinic Rochester Minnesota 55905 United States of America

Department of Internal Medicine Division of Cardiovascular Medicine Mayo Clinic Rochester Minnesota 55905 United States of America; Department of Physiology and Biomedical Engineering Mayo Clinic Rochester Minnesota 55905 United States of America

International Clinical Research Center Department of Cardiovascular Diseases St Anne's University Hospital Brno Czech Republic; Department of Anesthesiology and Intensive Care St Anne's University Hospital Masaryk University Brno Czech Republic

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