BDNF secretion by human pulmonary artery endothelial cells in response to hypoxia

Abstract

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 72h exposure to high altitude (~11,000 ft, alveolar PO2=100mmHg) 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 100μM 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.

Circulating Brain-Derived Neurotrophic Factor Has Diagnostic and Prognostic Value in Traumatic Brain Injury

“…Although circulating BDNF may originate from the hippocampus, cerebral cortex, and basal forebrain, 58 it also may be derived from other cellular sources, including platelets, 59,60 smooth muscle cells, 35,61 and vascular endothelial cells. 62 This supports BDNF's role as a promoter of neuronal growth and survival both in the central and peripheral nervous system. However, it is unclear whether circulating BDNF values measured in this study are representative of central nervous system values.…”

The influence of a mild thermal challenge and severe hypoxia on exercise performance and serum BDNF

“…In terms of physiological and perceptual measures, a self-paced performance test will allow participants to regulate power output in such a way that the physiological and perceptual strain should be similar. For BDNF we expect an increase due to the combination of the higher ambient temperature and exercise (as was shown in the research of Goekint et al 2011), and even a possible further rise due to the addition of the altitude stressor (Helan et al 2014). The acute increase in BDNF is, however, expected to be small, and as such we further hypothesized that this would not be linked to an improved cognitive performance.…”

“…Two studies looked at the effects of chronic altitude exposure for at least 72 h (Li et al 2012;Helan et al 2014). Their outcomes are contradictory, Li et al (2012) showed a decrease in BDNF concentration after a 5-day acclimatization period at 3900 m, while Helan et al (2014) observed increased BDNF levels after 72 h at 3350 m. Both hypoxia and BDNF increased hypoxia-inducible factor 1 (Helan et al 2014), a factor that is considered as an important regulator in the hypoxic response of the BBB (Ogunshola and Al-Ahmad 2012). The discrepancy in these findings and the lack of effect on an acute exposure, as observed in the present study, elucidate the necessity for further research on the effects of altitude on BDNF, and the potential mechanisms involved.…”

“…The effect of altitude on BDNF has not been the topic of many studies. Helan et al (2014) reported an increase in BDNF after chronic (72 h) exposure to 15 % hypoxia (~88 %). Both hypoxia and BDNF increased hypoxia-inducible factor 1 (Helan et al 2014), a factor that is considered as an important regulator in the hypoxic response of the BBB (Ogunshola and Al-Ahmad 2012).…”

“…Helan et al (2014) reported an increase in BDNF after chronic (72 h) exposure to 15 % hypoxia (~88 %). Both hypoxia and BDNF increased hypoxia-inducible factor 1 (Helan et al 2014), a factor that is considered as an important regulator in the hypoxic response of the BBB (Ogunshola and Al-Ahmad 2012). Indeed, as observed in higher ambient temperature, also a hypoxic stimulus has been shown to increase BBB permeability (Natah et al 2009).…”