Gestational Hypoxia Increases Reactive Oxygen Species and Inhibits Steroid Hormone-Mediated Upregulation of Ca2+-Activated K+ Channel Function in Uterine Arteries

Gestational hypoxia inhibits steroid hormone-induced upregulation of Ca2+-activated K+ (K-Ca) channel activities in uterine arteries. We tested the hypothesis that increased reactive oxygen species play an important role in hypoxia-mediated inhibition of K-Ca channel activities. Uterine arteries were isolated from nonpregnant (nonpregnant uterine artery) and near-term (approximate to 142-145 day) pregnant (pregnant uterine artery) sheep maintained at either sea level or high altitude (3820 m, Pao(2) : 60 mm Hg) for 110 days. In pregnant uterine arteries, hypoxia significantly decreased large conductance channel opener NS1619-and small conductance channel opener NS309-induced relaxations, which were partially restored by reactive oxygen species inhibitor N-acetylcysteine (NAC). NAC significantly increased large conductance K-Ca but not small conductance K-Ca current densities in uterine arterial smooth muscle cells in pregnant animals acclimatized to high altitude. The NAC-sensitive component of small conductance K-Ca-induced relaxations was diminished in endothelium-denuded arteries. In nonpregnant uterine arteries, NS1619-and NS309-induced relaxations were diminished compared with those in pregnant uterine arteries. Treatment of nonpregnant uterine arteries with 17 beta-estradiol and progesterone for 48 hours increased small conductance K-Ca type 3 protein abundance and NS1619-and NS309-induced relaxations, which were inhibited by hypoxia. This hypoxiamediated inhibition was reversed by NAC. Consistently, steroid hormone treatment had no significant effects on large conductance K-Ca current density in nonpregnant uterine arteries of hypoxic animals in the absence of NAC but significantly increased it in the presence of NAC. These results suggest an important role of hypoxia-mediated reactive oxygen species in negatively regulating steroid hormone-mediated upregulation of K-Ca channel activity and adaptation of uterine vascular reactivity in pregnancy, which may contribute to the increased incidence of preeclampsia and fetal intrauterine growth restriction associated with gestational hypoxia.