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Abstract
BackgroundHypoxia 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 Results48h 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.ConclusionsEnhanced 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.
Highlights
Enhanced expression and signaling of the brain-derived neurotrophic factor (BDNF)-TrkB system in pulmonary artery smooth muscle cells (PASMCs) is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function
The BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and a potential target for therapy
ELISA of the supernatant from PASMCs exposed to normoxia vs. hypoxia (1% O2 which is known to induce HIF1α; see below)[8,39,40] demonstrated baseline presence of BDNF with increased secretion following hypoxia (Fig 1D; n = 7 patients without pulmonary vascular disease; p
Summary
There is substantial interest in locally-produced growth factors (e.g. vascular endothelial growth factor) released within the PA in response to hypoxia with autocrine/paracrine effects on PASMCs.[12,13] In this regard, the family of neurotrophins, well-known in the nervous system,[14,15] may be relevant to the PA Neurotrophins act via both high-affinity tropomyosin related kinase (Trk) and low-affinity p75NTR receptors, activating pathways including phospholipase C, PI3 kinase, mitogen activated protein kinases (MAPK), and NFκB.[15,16] They can genomically and non-genomically alter [Ca2+]i[17] as well as cell proliferation, survival and migration.[15,18] There is increasing evidence (including our own) that neurotrophins such as brain-derived neurotrophic factor (BDNF) and their receptors (TrkB) are expressed and functional within the airways and pulmonary vasculature.[19,20,21,22] For example, Kwapiszewska et al reported that BDNF/TrkB interactions can augment PASMC cell proliferation in idiopathic pulmonary hypertension. We examined the effect of hypoxia on BDNF in humans, and the influence of hypoxiaenhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs)
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