Chronic hypoxia suppresses pregnancy-induced upregulation of large-conductance Ca2+-activated K+ channel activity in uterine arteries.
Our previous study demonstrated that increased Ca(2+)-activated K(+) (BK(Ca)) channel activity played a key role in the normal adaptation of reduced myogenic tone of uterine arteries in pregnancy. The present study tested the hypothesis that chronic hypoxia during gestation inhibits pregnancy-induced upregulation of BK(Ca) channel function in uterine arteries. Resistance-sized uterine arteries were isolated from nonpregnant and near-term pregnant sheep maintained at sea level (≈ 300 m) or exposed to high-altitude (3801 m) hypoxia for 110 days. Hypoxia during gestation significantly inhibited pregnancy-induced upregulation of BK(Ca) channel activity and suppressed BK(Ca) channel current density in pregnant uterine arteries. This was mediated by a selective downregulation of BK(Ca) channel β1 subunit in the uterine arteries. In accordance, hypoxia abrogated the role of the BK(Ca) channel in regulating pressure-induced myogenic tone of uterine arteries that was significantly elevated in pregnant animals acclimatized to chronic hypoxia. In addition, hypoxia abolished the steroid hormone-mediated increase in the β1 subunit and BK(Ca) channel current density observed in nonpregnant uterine arteries. Although the activation of protein kinase C inhibited BK(Ca) channel current density in pregnant uterine arteries of normoxic sheep, this effect was ablated in the hypoxic animals. The results demonstrate that selectively targeting BK(Ca) channel β1 subunit plays a critical role in the maladaption of uteroplacental circulation caused by chronic hypoxia, which contributes to the increased incidence of preeclampsia and fetal intrauterine growth restriction associated with gestational hypoxia.
Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA. lzhang@llu.edu
Xiang-Qun
XQ
Hu
Daliao
D
Xiao
Ronghui
R
Zhu
Xiaohui
X
Huang
Shumei
S
Yang
Sean M
SM
Wilson
Lubo
L
Zhang
D015761:4-Aminopyridine / Q000494:pharmacology; D000064:Acclimatization / Q000502:physiology; D000531:Altitude; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002908:Chronic Disease; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D012756:Sheep; D019789:Tetraethylammonium / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation; D055988:Uterine Artery / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D010455:Peptides; D026902:Potassium Channel Blockers; D015240:Phorbol 12,13-Dibutyrate; D011374:Progesterone; D004958:Estradiol; D019789:Tetraethylammonium; C064719:iberiotoxin; D015761:4-Aminopyridine; D011493:Protein Kinase C