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.

• MeSH
• arteria pulmonalis cytologie   MeSH
• hypoxie buňky účinky léků   MeSH
• lidé MeSH
• membránové glykoproteiny metabolismus   MeSH
• mozkový neurotrofický faktor metabolismus   MeSH
• myocyty hladké svaloviny cytologie   účinky léků   metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• receptor trkB MeSH
• regulace genové exprese účinky léků   MeSH
• tyrosinkinasy metabolismus   MeSH
• vápník metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• BDNF protein, human MeSH Prohlížeč
• membránové glykoproteiny MeSH
• mozkový neurotrofický faktor MeSH
• receptor trkB MeSH
• tropomyosin-related kinase-B, human MeSH Prohlížeč
• tyrosinkinasy MeSH
• vápník MeSH

Within human pulmonary artery, neurotrophin growth factors [NTs; e.g. brain-derived neurotrophic factor (BDNF)] and their high-affinity receptors (tropomyosin-related kinase; Trk) and low-affinity receptors p75 neurotrophin receptor (p75NTR) have been reported, but their functional role is incompletely understood. We tested the hypothesis that BDNF is produced by human pulmonary artery endothelial cells (PAECs). In the context of hypoxia as a risk factor for pulmonary hypertension, we examined the effect of hypoxia on BDNF secretion and consequent autocrine effects on pulmonary endothelium. Initial ELISA analysis of circulating BDNF in 30 healthy human volunteers showed that 72 h exposure to high altitude (~11,000 ft, alveolar PO2 = 100 mmHg) results in higher BDNF compared to samples taken at sea level. Separately, in human PAECs exposed for 24h to normoxia vs. hypoxia (1-3% O2), ELISA of extracellular media showed increased BDNF levels. Furthermore, quantitative PCR of PAECs showed 3-fold enhancement of BDNF gene transcription with hypoxia. In PAECs, BDNF induced NO production (measured using an NO-sensitive fluorescent dye DAF2-DA) that was significantly higher under hypoxic conditions, an effect also noted with the TrkB agonist 7,8-DHF. Importantly, hypoxia-induced NO was blunted by neutralization of secreted BDNF using the chimeric TrkB-Fc. Both hypoxia and BDNF increased iNOS (but not eNOS) mRNA expression. In accordance, BDNF enhancement of NO in hypoxia was not blunted by 50 nM L-NAME (eNOS inhibition) but substantially lower with 100 μM L-NAME (eNOS and iNOS inhibition). Hypoxia and BDNF also induced expression of hypoxia inducible factor 1 alpha (HIF-1α), a subunit of the transcription factor HIF-1, and pharmacological inhibition of HIF-1 diminished hypoxia effects on BDNF expression and secretion, and NO production. These results indicate that human PAECs express and secrete BDNF in response to hypoxia via a HIF-1-regulated pathway.

• Klíčová slova
• Hypoxia inducible factor 1, Neurotrophin, Nitric oxide, Tropomyosin related kinase, eNOS, iNOS,
• MeSH
• arginasa metabolismus   MeSH
• arteria pulmonalis patologie   MeSH
• cévní endotel patologie   MeSH
• endoteliální buňky metabolismus   MeSH
• exprese genu MeSH
• faktor 1 indukovatelný hypoxií metabolismus   MeSH
• hypoxie buňky MeSH
• hypoxie krev   MeSH
• kultivované buňky MeSH
• lidé MeSH
• membránové glykoproteiny MeSH
• messenger RNA genetika   metabolismus   MeSH
• mozkový neurotrofický faktor krev   genetika   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• proteinkinasy metabolismus   MeSH
• receptor trkB MeSH
• signální transdukce MeSH
• synthasa oxidu dusnatého, typ II metabolismus   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• tyrosinkinasy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• ARG1 protein, human MeSH Prohlížeč
• ARG2 protein, human MeSH Prohlížeč
• arginasa MeSH
• BDNF protein, human MeSH Prohlížeč
• faktor 1 indukovatelný hypoxií MeSH
• membránové glykoproteiny MeSH
• messenger RNA MeSH
• mozkový neurotrofický faktor MeSH
• NOS2 protein, human MeSH Prohlížeč
• NOS3 protein, human MeSH Prohlížeč
• oxid dusnatý MeSH
• proteinkinasy MeSH
• receptor trkB MeSH
• synthasa oxidu dusnatého, typ II MeSH
• synthasa oxidu dusnatého, typ III MeSH
• tropomyosin-related kinase-B, human MeSH Prohlížeč
• tyrosinkinasy MeSH