Center for Reproductive Health Sciences, Department of Obstetrics and Gynecology, Washington University in St Louis School of Medicine, St Louis, MO, 63110, USA.
J Physiol. 2018 Mar 15;596(6):1019-1033. doi: 10.1113/JP274524. Epub 2018 Feb 12.
The uterine artery (UA) markedly vasodilates during pregnancy to direct blood flow to the developing fetus. Inadequate UA vasodilatation leads to intrauterine growth restriction and fetal death. The large-conductance voltage- and Ca -activated K (BK ) channel promotes UA vasodilatation during pregnancy. We report that BK channel activation increases the UA diameter at late pregnancy stages in mice. Additionally, a BK channel auxiliary subunit, γ1, participates in this process by increasing channel activation and inducing UA vasodilatation at late pregnancy stages. Our results highlight the importance of the BK channel and its γ1-subunit for UA functional changes during pregnancy.
Insufficient vasodilatation of the uterine artery (UA) during pregnancy leads to poor utero-placental perfusion, contributing to intrauterine growth restriction and fetal loss. Activity of the large-conductance Ca -activated K (BK ) channel increases in the UA during pregnancy, and its inhibition reduces uterine blood flow, highlighting a role of this channel in UA adaptation to pregnancy. The auxiliary γ1-subunit increases BK activation in vascular smooth muscle, but its role in pregnancy-associated UA remodelling is unknown. We explored whether the BK and its γ1-subunit contribute to UA remodelling during pregnancy. Doppler imaging revealed that, compared to UAs from wild-type (WT) mice, UAs from BK knockout (BK ) mice had lower resistance at pregnancy day 14 (P14) but not at P18. Lumen diameters were twofold larger in pressurized UAs from P18 WT mice than in those from non-pregnant mice, but this difference was not seen in UAs from BK mice. UAs from pregnant WT mice constricted 20-50% in response to the BK blocker iberiotoxin (IbTX), whereas UAs from non-pregnant WT mice only constricted 15%. Patch-clamp analysis of WT UA smooth muscle cells confirmed that BK activity increased over pregnancy, showing three distinct voltage sensitivities. The γ1-subunit transcript increased 7- to 10-fold during pregnancy. Furthermore, γ1-subunit knockdown reduced IbTX sensitivity in UAs from pregnant mice, whereas γ1-subunit overexpression increased IbTX sensitivity in UAs from non-pregnant mice. Finally, at P18, γ1-knockout (γ1 ) mice had smaller UA diameters than WT mice, and IbTX-mediated vasoconstriction was prevented in UAs from γ1 mice. Our results suggest that the γ1-subunit increases BK activation in UAs during pregnancy.
子宫动脉（UA）在怀孕期间明显扩张，以将血液直接输送到发育中的胎儿。UA 扩张不足会导致宫内生长受限和胎儿死亡。大电导电压和 Ca 激活的 K（BK）通道在怀孕期间促进 UA 扩张。我们报告说，BK 通道的激活会增加怀孕后期小鼠 UA 的直径。此外，BK 通道辅助亚基γ1 通过增加通道的激活并在怀孕后期诱导 UA 扩张来参与此过程。我们的结果强调了 BK 通道及其 γ1 亚基在怀孕期间 UA 功能变化中的重要性。
怀孕期间 UA 扩张不足会导致胎盘灌注不良，导致宫内生长受限和胎儿丢失。怀孕期间 UA 中的大电导 Ca 激活的 K（BK）通道活性增加，其抑制会减少子宫血流量，这突出了该通道在 UA 适应怀孕中的作用。辅助γ1 亚基增加了血管平滑肌中 BK 的激活，但它在与怀孕相关的 UA 重塑中的作用尚不清楚。我们探讨了 BK 及其γ1 亚基是否有助于怀孕期间 UA 的重塑。多普勒成像显示，与野生型（WT）小鼠的 UA 相比，BK 敲除（BK）小鼠的 UA 在妊娠第 14 天（P14）时阻力较低，但在 P18 时则没有。与非怀孕小鼠相比，来自 P18 WT 小鼠的加压 UA 的管腔直径大两倍，但在 BK 小鼠的 UA 中则没有。怀孕 WT 小鼠的 UA 对 BK 阻滞剂 Iberiotoxin（IbTX）的反应收缩了 20-50％，而非怀孕 WT 小鼠的 UA 仅收缩了 15％。对 WT UA 平滑肌细胞的膜片钳分析证实，BK 活性在怀孕期间增加，显示出三种不同的电压敏感性。γ1 亚基转录物在怀孕期间增加了 7-10 倍。此外，在怀孕的小鼠中，γ1 亚基敲低降低了 IbTX 的敏感性，而在非怀孕的小鼠中，γ1 亚基过表达增加了 IbTX 的敏感性。最后，在 P18 时，γ1 敲除（γ1）小鼠的 UA 直径小于 WT 小鼠，并且 IbTX 介导的血管收缩在γ1 小鼠的 UA 中被阻止。我们的结果表明，γ1 亚基在怀孕期间增加了 UA 中的 BK 激活。
