The large-conductance voltage- and Ca 2+ -activated K + channel and its γ1-subunit modulate mouse uterine artery function during pregnancy

Abstract

Key points: 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 2+ -activated K + (BK Ca ) channel promotes UA vasodilatation during pregnancy. We report that BK Ca channel activation increases the UA diameter at late pregnancy stages in mice. Additionally, a BK Ca 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 Ca channel and its γ1-subunit for UA functional changes during pregnancy. Abstract: 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 2+ -activated K + (BK Ca ) 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 Ca activation in vascular smooth muscle, but its role in pregnancy-associated UA remodelling is unknown. We explored whether the BK Ca 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 Ca knockout (BK Ca−/− ) 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 Ca−/− mice. UAs from pregnant WT mice constricted 20–50% in response to the BK Ca 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 Ca 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 Ca activation in UAs during pregnancy.