Abstract
Insufficient vasodilation 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+ (BKCa) 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 BKCa activation in vascular smooth muscle, but its role in pregnancy-associated UA remodelling is unknown. We explored whether the BKCa and its γ1-subunit contribute to UA remodelling during pregnancy. Doppler imaging revealed that, compared to UAs from wild-type (WT) mice, UAs from BKCa knockout (BKCa−/−) mice had lower resistance at pregnancy day 14 (P14) but not at P18. Lumen diameters were two-fold larger in pressurized UAs from P18 WT mice than in those from non-pregnant mice, but this difference was not seen in UAs from BKCa−/− mice. UAs from pregnant WT mice constricted 20–50% in response to the BKCa blocker iberiotoxin (IbTX), whereas UAs from non-pregnant WT mice only constricted 15%. Patch-clamp analysis of WT UA smooth muscle cells confirmed that BKCa activity increased over pregnancy, showing three distinct voltage-sensitivities. The γ1-subunit transcript increased 7-10-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 BKCa activation in UAs during pregnancy.
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