Direct effect of chronic hypoxia in suppressing large conductance Ca2+‐activated K+ channel activity in ovine uterine arteries via increasing oxidative stress
Key points Chronic hypoxia has a direct effect in down‐regulating the BKCa channel β1 subunit and inhibiting the BKCa channel activity in uterine arteries of pregnant sheep. Oxidative stress plays a causal role in hypoxia‐mediated suppression of BKCa channel function. The steroid hormone‐induced eff...
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Published in | The Journal of physiology Vol. 594; no. 2; pp. 343 - 356 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
London
Wiley Subscription Services, Inc
15.01.2016
John Wiley and Sons Inc |
Subjects | |
Online Access | Get full text |
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Summary: | Key points
Chronic hypoxia has a direct effect in down‐regulating the BKCa channel β1 subunit and inhibiting the BKCa channel activity in uterine arteries of pregnant sheep.
Oxidative stress plays a causal role in hypoxia‐mediated suppression of BKCa channel function.
The steroid hormone‐induced effect on BKCa channels is a target of hypoxia‐mediated oxidative stress.
Inhibition of oxidative stress ameliorates the adverse effect of hypoxia both ex vivo and in vivo in pregnant sheep exposed to long‐term high‐altitude hypoxia.
Our findings provide novel evidence of a causative role of oxidative stress in hypoxia‐mediated inhibition of the BKCa channel activity in uterine arteries and new insights in understanding and alleviating pregnancy complications associated with gestational hypoxia such as pre‐eclampsia and fetal growth restriction.
Uterine arteries of pregnant sheep acclimatized to long‐term high‐altitude hypoxia were associated with a decrease in large‐conductance Ca2+‐activated K+ (BKCa) channel activity. The present study tested the hypothesis that prolonged hypoxia has a direct effect in suppressing BKCa channel activity by increasing oxidative stress. Uterine arteries were isolated from non‐pregnant and near‐term (∼142 days) pregnant sheep, and were treated ex vivo with 21.0 or 10.5% O2 for 48 h. The hypoxia treatment significantly increased the production of reactive oxygen species in uterine arteries, which was blocked by N‐acetylcysteine. In uterine arteries of pregnant sheep, hypoxia significantly inhibited BKCa channel current density, decreased NS1619‐induced relaxations and increased pressure‐dependent tone, which were annulled by N‐acetylcysteine. In accordance, hypoxia resulted in down‐regulation of BKCa channel β1 subunit, which was restored in the presence of N‐acetylcysteine. In addition, the N‐acetylcysteine treatment significantly increased BKCa channel β1 subunit abundance and BKCa channel current density in uterine arteries from pregnant sheep exposed to high‐altitude hypoxia (3801 m, PaO2: 60 mmHg) for 110 days. In uterine arteries of non‐pregnant animals, hypoxia inhibited steroid hormone‐induced up‐regulation of BKCa channel current density and NS1619‐mediated relaxations, which were reversed by N‐acetylcysteine. Furthermore, the synthetic superoxide dismutase and catalase mimetic EUK‐134 also ablated the effects of hypoxia on BKCa channel currents in uterine arteries. The results demonstrate a direct effect of hypoxia in inhibiting the BKCa channel activity in uterine arteries via increased oxidative stress.
Key points
Chronic hypoxia has a direct effect in down‐regulating the BKCa channel β1 subunit and inhibiting the BKCa channel activity in uterine arteries of pregnant sheep.
Oxidative stress plays a causal role in hypoxia‐mediated suppression of BKCa channel function.
The steroid hormone‐induced effect on BKCa channels is a target of hypoxia‐mediated oxidative stress.
Inhibition of oxidative stress ameliorates the adverse effect of hypoxia both ex vivo and in vivo in pregnant sheep exposed to long‐term high‐altitude hypoxia.
Our findings provide novel evidence of a causative role of oxidative stress in hypoxia‐mediated inhibition of the BKCa channel activity in uterine arteries and new insights in understanding and alleviating pregnancy complications associated with gestational hypoxia such as pre‐eclampsia and fetal growth restriction. |
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ISSN: | 0022-3751 1469-7793 |
DOI: | 10.1113/JP271626 |