Chronic Hypoxia Suppresses Pregnancy-Induced Upregulation of Large-Conductance Ca ²⁺ -Activated K ⁺ Channel Activity in Uterine Arteries

Abstract

Our previous study demonstrated that increased Ca2+-activated K+ (BKCa) 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 BKCa 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 BKCa channel activity and suppressed BKCa channel current density in pregnant uterine arteries. This was mediated by a selective downregulation of BKCa channel β1 subunit in the uterine arteries. In accordance, hypoxia abrogated the role of the BKCa 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 BKCa channel current density observed in nonpregnant uterine arteries. Although the activation of protein kinase C inhibited BKCa channel current density in pregnant uterine arteries of normoxic sheep, this effect was ablated in the hypoxic animals. The results demonstrate that selectively targeting BKCa 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.

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

“…9). Such a correlation would indicate that the augmented role for BK Ca channels in the fetus and the attenuation of normal BK Ca relaxation in the newborn are brought on by hypoxia-induced changes in channel expression, as we observed in the uterine arteries of pregnant ewes (44). However, the tension and expression studies did not agree with one another.…”

“…APC-021, Alomone, Jerusalem, Israel) and 300:1 for BK-␤1 (catalog no. APC-036, Alomone) (44). For visualization, membranes were incubated for 90 min with a secondary antibody conjugated to DyLight 800 (catalog no.…”

“…The BK Ca channel is stimulated by ryanodine receptor-dependent Ca 2ϩ sparks and independently modulated by PKA and PKG downstream of sGC and cGMP (3,74,77,79). To establish the role of BK Ca channels in bradykinin-mediated vasorelaxation, arteries were treated with tetraethylammonium (TEA) at 1 mM, a concentration that blocks roughly one-half of the current due to BK Ca channels (44,46). Figure 9 shows the dose-dependent relaxation of PE-precontracted vessels to bradykinin in the presence and absence of 1 mM TEA.…”

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.…”

Cardiovascular Adaptation to High-Altitude Hypoxia

“…Studies in pregnant sheep model of long-term high-altitude (3801 m) exposure provide novel evidence that long-term high-altitude hypoxia during pregnancy adversely affects the uterine circulation via downregulating BKca channel function in uterine vasculatures [72]. High-altitude hypoxia during gestation significantly inhibited pregnancy-associated upregulation of BKca channel activity and attenuated BKca channel current density in pregnant uterine arteries [72]. This was mediated by a selective downregulation of BKca channel β1 subunit expression in the uterine arteries.…”