Potassium channels and uteroplacental vessels function in pregnant long QT type 1 women

项目摘要 长QT综合征（LQTS）是一种心脏通道病，易使个体发生室性心律失常， 心脏骤停1型LQTS（LQT 1）是由KCNQ 1或KCNE 1突变引起的，KCNQ 1或KCNE 1是编码电压- 门控K+（Kv7.1）通道和辅助亚基。携带致病性Kv7.1变体的母亲显示 与一般人群相比，胎儿生长受限和流产的发生率较高。Kv 7通道 已显示有助于人类胎盘血管的血管舒张，这对于维持 妊娠期间子宫胎盘灌注。Kv 7在胎盘绒毛膜板动脉中的表达减少， 妊娠并发症，如先兆子痫。然而，Kv7.1在血管舒张反应中的作用， 母体阻力血管（即，子宫肌层动脉）在正常或复杂的怀孕期间， 阐明。本实验室在健康和妊娠期子宫肌层动脉的血管反应性方面具有丰富的经验 并发症我们的初步数据表明，Kv7.1依赖性的绒毛膜板动脉血管舒张是一个重要的因素。 与健康对照组相比，一些LQT 1患者的血压降低。因此，我们假设功能受损 和/或子宫肌层和/或胎盘动脉中Kv7.1的表达是不良妊娠结局的基础 在LQT 1患者中观察到。为了验证这一假设，我们建议进行两个综合的科学目标。在Aim中 1，我们将讨论Kv7.1通道在子宫肌层和绒毛膜板动脉中的血管舒张作用， LQT 1或剖腹产后正常妊娠的妇女。我们将通过导丝在体外评估血管舒张 肌造影我们还将评估Kv 7和辅助蛋白在子宫肌层中的表达和定位， 胎盘组织目的2将确定子宫胎盘血流的临床超声指标是否可以预测 LQT 1女性的胎盘功能不全。我们将使用三维能量超声来评估子宫动脉血流 和胎盘血管化指数在三个不同胎龄（14，20和34周）的对照和 LQT 1女性。我们将这些测量与胎儿和新生儿的生物统计学和妊娠结局相关联。 从科学上讲，所提出的工作对于提高我们对潜在机制的理解至关重要。 在LQT 1女性中观察到胎儿生长减少和不良妊娠结局。我们的项目也 具有潜在的重要临床意义;特别是，我们的研究结果可能会发现新的治疗方法， 目标和诊断方法，以防止这些妊娠并发症。

PROJECT SUMMARY Long QT syndrome (LQTS) is a cardiac channelopathy that predispose individuals to ventricular arrhythmias and cardiac arrest. Type 1 LQTS (LQT1) is caused by mutations in KCNQ1 or KCNE1, genes that encode for voltage- gated K+ (Kv7.1) channels and auxiliary subunits, respectively. Mothers with pathogenic Kv7.1 variants show higher prevalence of fetal growth restriction and pregnancy loss compared to general population. Kv7 channels have been shown to contribute to the vasodilation of human placental vessels, which are important in maintaining uteroplacental perfusion during pregnancy. Kv7 expression in placental chorionic plate arteries is reduced in pregnancy complications such as preeclampsia. However, the role of Kv7.1 in vasodilatory responses in maternal resistance vessels (i.e., myometrial arteries) during normal or complicated pregnancies has not been elucidated. Our lab has extensive experience in vasoreactivity of myometrial arteries in healthy and pregnancy complications. Our preliminary data show that Kv7.1-dependent vasodilation of chorionic plate arteries is reduced in some LQT1 patients compared with healthy controls. Thus, we hypothesize that impaired function and/or expression of Kv7.1 in myometrial and/or placental arteries underlies the adverse pregnancy outcomes observed in LQT1 patients. To test this hypothesis, we propose to conduct two integrated scientific aims. In Aim 1, we will address the vasodilatory role of Kv7.1 channels in myometrial and chorionic plate arteries isolated from women with LQT1 or normal pregnancies after delivery by C-section. We will assess vasodilation in vitro via wire myography. We will also evaluate the Kv7 and ancillary proteins expression and localization in myometrial and placental tissue. Aim 2 will determine whether clinical ultrasound indices of uteroplacental blood flow can predict placental insufficiency in LQT1 women. We will use 3-D power ultrasound to assess uterine artery blood flow and placental vascularization indices at three different gestational ages (14, 20 and 34 weeks) in control and LQT1 women. We will correlate these measurements with fetal and neonatal biometry and pregnancy outcomes. Scientifically, the work proposed is vital to improving our understanding of the mechanisms underlying the reduced fetal growth and adverse pregnancy outcomes observed in LQT1 women. Our proposed project also has potentially important clinical implications; in particular, our study outcomes may identify novel therapeutic targets and diagnostic approaches to prevent these pregnancy complications.