The large-conductance voltage- and Ca2+ -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 Ca²⁺ -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 Ca²⁺ -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.

Keywords: BKCa channel; auxiliary subunits; pregnancy; uterine artery; utero-placental perfusion; vascular smooth muscle.