Chronic Hypoxia Inhibits Pregnancy-Induced Upregulation of SK _Ca Channel Expression and Function in Uterine Arteries

Abstract

Summary Small conductance Ca2+-activated K+ (SKCa) channels are crucial in regulating vascular tone and blood pressure. The present study tested the hypothesis that SKCa channels play an important role in uterine vascular adaptation in pregnancy, which is inhibited by chronic hypoxia during gestation. 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. Immunohistochemistry revealed the presence of SKCa channels type 2 (SK2) and type 3 (SK3) in both smooth muscle and endothelium of uterine arteries. The expression of SK2 and SK3 channels was significantly increased during pregnancy, which was inhibited by chronic hypoxia. In normoxic animals, both SKCa channel opener NS309 and a large-conductance (BKCa) channel opener NS1619 relaxed norepinephrine-contracted uterine arteries in pregnant but not nonpregnant sheep. These relaxations were inhibited by selective SKCa and BKCa channel blockers, respectively. NS309-induced relaxation was largely endothelium-independent. In high altitude hypoxic animals, neither NS1691 nor NS309 produced significant relaxation of uterine arteries in either nonpregnant or pregnant sheep. Similarly, the role of SKCa channels in regulating myogenic reactivity of uterine arteries in pregnant animals was abrogated by chronic hypoxia. Accordingly, the enhanced SKCa channel activity in uterine arterial myocytes of pregnant animals was ablated by chronic hypoxia. The findings suggest a novel mechanism of SKCa channels in regulating myogenic adaptation of uterine arteries in pregnancy, and in the maladaptation of uteroplacental circulation caused by chronic hypoxia during gestation.

Impairment of IKCachannels contributes to uteroplacental endothelial dysfunction in rat diabetic pregnancy

“…1). Rat uteroplacental arteries were also almost 10 times more sensitive to NS309 than uterine arteries of pregnant sheep (54). In addition, in our study, NS309-induced vasodilation of rat arteries was abolished by endothelial denudation and was therefore mediated by SK Ca /IK Ca channels located on the vascular endothelium.…”

“…In addition, in our study, NS309-induced vasodilation of rat arteries was abolished by endothelial denudation and was therefore mediated by SK Ca /IK Ca channels located on the vascular endothelium. In contrast, the relaxation in response to NS309 was preserved in denuded uterine vessels of pregnant sheep, indicating the major role of Ca 2ϩ -activated channels on vascular SMCs (54). These data suggest that cellular localization and function of SK Ca /IK Ca channels in the maternal uterine vasculature may be different in species with hemochorial versus epitheliochorial placentation.…”

Maternal Vascular Physiology in Preeclampsia

“…107 Upregulation of Ca 2+ -activated K + (K Ca ) channels via steroid hormone-dependent mechanisms may contribute to pregnancy-mediated increases in EDH-dependent uterine artery dilation. 108 Gestational hypoxia inhibits BK Ca and SK Ca channel upregulation, 109,110 and this may be because of pathways mediated by reactive oxygen species. 111 Considering that preeclampsia is associated with hypoxia and is a state of oxidative stress, these results may have implications for preeclampsia.…”

Sightings edited by John W. Severinghaus

“…Zhu et al (2013) isolated uterine arteries from nonpregnant and near-term pregnant sheep maintained at sea level ( approximately 300 m) or exposed to high-altitude (3801 m) hypoxia for 110 days. The expression of type 2 (SK2) and type 3 (SK3) channels was significantly increased during normoxic pregnancy but was inhibited by chronic hypoxia.…”