The large‐conductance voltage‐ and Ca²⁺‐activated K⁺ channel and its γ1‐subunit modulate mouse uterine artery function 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 -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.

Oxytocin can regulate myometrial smooth muscle excitability by inhibiting the Na+‐activated K+ channel, Slo2.1

“…; Lorca et al . ), we treated the cells with the SLO1 blocker tetraethylammonium (TEA) (5–10 m m ). These experiments revealed two components of the macroscopic current: a TEA‐sensitive current and a TEA‐resistant current (Fig.…”

“…1A, Control). Because we suspected that part of this current was conducted by the large-conductance Ca 2+ -activated K + channel SLO1 (BK Ca , MaxiK), which is expressed in hMSMCs (Khan et al 1993;Khan et al 1998;Brainard et al 2009;Lorca et al 2014;Lorca et al 2014;Wakle-Prabagaran et al 2016;Lorca et al 2017;Lorca et al 2018), we treated the cells with the SLO1 blocker tetraethylammonium (TEA) (5-10 mM). These experiments revealed two components of the macroscopic current: a TEA-sensitive current and a TEA-resistant current (Fig.…”

Preeclampsia link to gestational hypoxia

“…99,[101][102][103] Maternal treatment with MitoQ in animal models of chronic hypoxia has led to the improvement of both placental mitochondrial stress and fetal outcomes, including birth weight and developmental programming of cardiovascular and psychiatric diseases, highlighting the importance of mitochondrial stress in mediating hypoxia-induced pathology. 67,77,99 Calcium-activated potassium channels During pregnancy, Ca 2 + -activated K + (BK Ca ) channels in vascular smooth muscle cells have gained traction in being important mediators of uterine artery vasodilatation, and their inhibition reduces uteroplacental blood flow, contributing to IUGR 104 (Fig. 1).…”

Plasticity of the Maternal Vasculature During Pregnancy

“…Small-conductance Ca 2+ -activated K + (SK Ca ) type 2 and type 3 channels are expressed in uterine artery VSMCs and were significantly increased during pregnancy by steroid hormone (145). Similarly, large-conductance Ca 2+ -activated K + (BK Ca ) channels in uterine artery VSMCs were upregulated during pregnancy, with 7- to 10-fold increases in the BK Ca γ1-subunit transcript (146). Notably, activation of both SK Ca and BK Ca channels relaxed norepinephrine-preconstricted uterine arteries in pregnant sheep, but not in nonpregnant sheep, in an endothelium-independent manner (147).…”