Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Cardiovasc Res. 2021 Feb 22;117(3):792-804. doi: 10.1093/cvr/cvaa089.
Our recent study demonstrated that increased Ca2+ sparks and spontaneous transient outward currents (STOCs) played an important role in uterine vascular tone and haemodynamic adaptation to pregnancy. The present study examined the role of ryanodine receptor (RyR) subtypes in regulating Ca2+ sparks/STOCs and myogenic tone in uterine arterial adaptation to pregnancy.
Uterine arteries isolated from non-pregnant and near-term pregnant sheep were used in the present study. Pregnancy increased the association of α and β1 subunits of large-conductance Ca2+-activated K+ (BKCa) channels and enhanced the co-localization of RyR1 and RyR2 with the β1 subunit in the uterine artery. In contrast, RyR3 was not co-localized with BKCa β1 subunit. Knockdown of RyR1 or RyR2 in uterine arteries of pregnant sheep downregulated the β1 but not α subunit of the BKCa channel and decreased the association of α and β1 subunits. Unlike RyR1 and RyR2, knockdown of RyR3 had no significant effect on either expression or association of BKCa subunits. In addition, knockdown of RyR1 or RyR2 significantly decreased Ca2+ spark frequency, suppressed STOCs frequency and amplitude, and increased pressure-dependent myogenic tone in uterine arteries of pregnant animals. RyR3 knockdown did not affect Ca2+ sparks/STOCs and myogenic tone in the uterine artery.
Together, the present study demonstrates a novel mechanistic paradigm of RyR subtypes in the regulation of Ca2+ sparks/STOCs and uterine vascular tone, providing new insights into the mechanisms underlying uterine vascular adaptation to pregnancy.
我们最近的研究表明，钙火花和自发性瞬间外向电流（STOCs）的增加在子宫血管张力和血流动力学适应妊娠中起着重要作用。本研究探讨了兰尼碱受体（RyR）亚型在调节钙火花/STOCs 和子宫动脉对妊娠的肌源性张力中的作用。
本研究使用了来自非妊娠和近足月妊娠绵羊的子宫动脉。妊娠增加了大电导钙激活钾（BKCa）通道的α和β1 亚基的缔合，并增强了 RyR1 和 RyR2 与子宫动脉中β1 亚基的共定位。相比之下，RyR3 与 BKCaβ1 亚基没有共定位。在妊娠绵羊的子宫动脉中敲低 RyR1 或 RyR2 会下调 BKCa 通道的β1 亚基而不是α亚基，并减少α和β1 亚基的缔合。与 RyR1 和 RyR2 不同，RyR3 的敲低对 BKCa 亚基的表达或缔合均无显著影响。此外，RyR1 或 RyR2 的敲低显著降低了钙火花频率，抑制了 STOCs 的频率和幅度，并增加了妊娠动物子宫动脉的压力依赖性肌源性张力。RyR3 的敲低对子宫动脉中的钙火花/STOCs 和肌源性张力没有影响。
综上所述，本研究展示了 RyR 亚型在调节钙火花/STOCs 和子宫血管张力中的新型机制范例，为子宫血管适应妊娠的机制提供了新的见解。
