Preferential activation of HIF-2α adaptive signalling in neuronal-like cells in response to acute hypoxia

Stroke causes severe neuronal damage as disrupted cerebral blood flow starves neurons of oxygen and glucose. The hypoxia inducible factors (HIF-1α and HIF-2α) orchestrate oxygen homeostasis and regulate specific aspects of hypoxic adaptation. Here we show the importance of HIF-2α dependant signallin...

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Bibliographic Details
Published in:PloS one 2017-10, Vol.12 (10), p.e0185664-e0185664
Main Authors: Martín-Aragón Baudel, Miguel A S, Rae, Mick T, Darlison, Mark G, Poole, Amy V, Fraser, Jennifer A
Format: Article
Language:English
Subjects:
Adaptation
Adaptation, Physiological
Angiogenesis
Animals
Apoptosis
Basic Helix-Loop-Helix Transcription Factors - metabolism
Biology and Life Sciences
Biomarkers
Blood flow
CD44 antigen
Cell cycle
Cell Differentiation
Cell division
Cell Hypoxia
Cerebral blood flow
Differentiation
Endoplasmic Reticulum Stress
Gene expression
Growth factors
Homeostasis
Humans
Hypoxia
Hypoxia-inducible factor 1
Hypoxia-inducible factor 1a
Immunoblotting
Ischemia
Medicine and Health Sciences
Molecular modelling
Nerve growth factor
Neural stem cells
Neural Stem Cells - metabolism
Neurogenesis
Neurons - cytology
Neurons - metabolism
Neurotrophin 2
Oxygen
Penicillin
Potassium-chloride cotransporter
Protein Stability
Rats
Real-Time Polymerase Chain Reaction
Regression analysis
Research and Analysis Methods
Retinoic acid
Rodents
Signal Transduction
Signaling
Stem cells
Stroke
Transcription
Veins & arteries
Vimentin
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Summary:Stroke causes severe neuronal damage as disrupted cerebral blood flow starves neurons of oxygen and glucose. The hypoxia inducible factors (HIF-1α and HIF-2α) orchestrate oxygen homeostasis and regulate specific aspects of hypoxic adaptation. Here we show the importance of HIF-2α dependant signalling in neuronal adaptation to hypoxic insult. PC12 and NT2 cells were differentiated into neuronal-like cells using NGF and retinoic acid, and exposed to acute hypoxia (1% O2). Gene and protein expression was analysed by qPCR and immunoblotting and the neuronal-like phenotype was examined. PC12 and NT2 differentiation promoted neurite extension and expression of neuronal markers, NSE and KCC2. Induction of HIF-1α mRNA or protein was not detected in hypoxic neuronal-like cells, however marked induction of HIF-2α mRNA and protein expression was observed. Induction of HIF-1α target genes was also not detected in response to acute hypoxia, however significant induction of HIF-2α transcriptional targets was clearly evident. Furthermore, hypoxic insult dramatically reduced both neurite number and length, and attenuated expression of neuronal markers, NSE and KCC2. This correlated with an increase in expression of the neural progenitor and stem cell-like markers, CD44 and vimentin, suggesting HIF-2α molecular mechanisms could potentially promote regression of neuronal-like cells to a stem-like state and trigger neuronal recovery following ischaemic insult. Our findings suggest the HIF-2α pathway predominates over HIF-1α signalling in neuronal-like cells following acute hypoxia.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0185664