TY - JOUR
T1 - Role of hypoxia-induced brain derived neurotrophic factor in human pulmonary artery smooth muscle
AU - Hartman, William
AU - Helan, Martin
AU - Smelter, Dan
AU - Sathish, Venkatachalem
AU - Thompson, Michael
AU - Pabelick, Christina M.
AU - Johnson, Bruce
AU - Prakash, Y. S.
N1 - Publisher Copyright:
© 2015 Hartman et al.
PY - 2015/7/20
Y1 - 2015/7/20
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0129489
DO - 10.1371/journal.pone.0129489
M3 - Article
C2 - 26192455
AN - SCOPUS:84941308735
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 7
M1 - e0129489
ER -