Myometrial artery potassium channel activity in intrauterine growth restriction pregnancy

宫内生长受限妊娠中子宫肌动脉钾通道活性

• 批准号: 10308093
• 负责人: Ramon Lorca
• 金额: $ 7.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308093
• 关键词: Acetylcholine; Acute; Address; Adverse effects; Area; Arteries; Birth Weight; Blood Vessels; Blood flow; Bradykinin; Brain; Cardiovascular Diseases; Cesarean section; Clinical; Data; Diagnosis; Drug Targeting; Elderly; Family; Fetal Growth; Fetal Growth Retardation; Foundations; Frequencies; Gestational Age; Glyburide; Goals; Growth and Development function; Head circumference; Human; Image; Immunohistochemistry; Impairment; Individual; Ion Channel; Knock-out; Lead; Left; Length; Life; Litter Size; Measures; Mediating; Modeling; Molecular; Molecular Target; Mothers; Myography; Myometrial; Outcome Study; Participant; Patch-Clamp Techniques; Perfusion; Pharmacology; Physiological; Placenta; Play; Population; Potassium Channel; Pregnancy; Process; Regulation; Reporting; Reproductive Health; Research; Resistance; Risk; Role; Smooth Muscle; Smooth Muscle Myocytes; Structure of umbilical artery; Testing; Therapeutic; Thromboxanes; Tissues; Uterus; Vascular Smooth Muscle; Vascular resistance; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Western Blotting; Wild Type Mouse; Woman; Work; adverse outcome; base; cardiovascular disorder risk; fetal; fluorophore; iberiotoxin; improved; indexing; neonatal death; new therapeutic target; novel; perinatal complications; perinatal period; prevent; protein expression; reduced uteroplacental blood flow; response; stillbirth; therapeutically effective; therapy development

PROJECT SUMMARY Intrauterine growth restriction (IUGR) increases the risk of stillbirth and neonatal death. The adverse effects of being born IUGR extend well beyond the perinatal period, increasing the risk of cardiovascular disease, among others, in later life. Currently, no effective strategies exist to prevent or treat IUGR. Our overarching goal is to determine the role of K+ channels and intracellular Ca2+ in the regulation of myometrial artery vasoreactivity, both important contributors to uteroplacental perfusion, and, in turn, fetal growth. We expect that two of the most prevalent K + channels in uterine vasculature, BK Ca and K ATP channels, will be impaired in IUGR pregnancy, in association with reduced MA vasorelaxation and fetal growth. To address this goal, we propose to conduct two integrated scientific aims. In Aim 1, we will determine whether (1) the vasodilatory role of BKCa and/or KATP channels is diminished in myometrial arteries from IUGR pregnancies compared to uncomplicated pregnancies; (2) K+ currents mediated by BKCa and/or KATP channels are reduced in myometrial artery smooth muscle cells from IUGR compared to uncomplicated pregnancies; and (3) IUGR impairs the protein expression and/or localization of these channels in myometrial arteries and placenta. Aim 2 will address the role of store- operated Ca2+ entry and intracellular Ca2+ stores in myometrial arteries from IUGR by asking whether myometrial artery smooth muscle cells from IUGR pregnancies show dysregulated store-operated Ca2+ entry and/or intracellular Ca2+ stores. Participants will be women with uncomplicated or IUGR pregnancies. Scientifically, the work proposed is vital to improving our understanding of the mechanisms underlying the reduced uteroplacental blood flow observed in IUGR pregnancies. Our proposed project also has potentially important clinical implications; in particular, our study outcomes may identify novel therapeutic targets to treat or prevent IUGR.

项目总结 胎儿宫内生长受限(IUGR)会增加死产和新生儿死亡的风险。的不利影响 出生时胎儿宫内发育迟缓远远超过围产期，增加了心血管疾病的风险，例如 其他人，在以后的生活中。目前，还没有有效的策略来预防或治疗IUGR。我们的首要目标是 确定K+通道和细胞内钙离子在子宫肌层动脉血管反应性调节中的作用 两者都是子宫胎盘灌注的重要因素，进而促进胎儿生长。我们预计这两个人 的 这个 多数 盛行 K + 频道 在……里面 子宫 血管系统， BK 钙 和 K ATP 频道， 将在IUGR中受损 妊娠，与MA血管松弛和胎儿生长减少有关。为了实现这一目标，我们建议 进行两个综合的科学目标。在目标1中，我们将确定(1)BKCa的血管扩张作用 与未合并并发症相比，IUGR妊娠患者子宫肌层动脉中KATP通道减少 (2)子宫肌层动脉平滑时，BKCa和/或KATP通道介导的K+电流减少 IUGR的肌细胞与非并发症妊娠的比较；以及(3)IUGR削弱了蛋白的表达 和/或这些通道在子宫肌层动脉和胎盘中的定位。目标2将解决商店的角色- IUGR子宫肌层动脉的钙离子内流和细胞内钙储存 IUGR妊娠的子宫肌层动脉平滑肌细胞显示异常的钙离子内流 和/或细胞内钙存储。参与者将是无并发症或IUGR怀孕的妇女。 从科学上讲，拟议的工作对于提高我们对 IUGR妊娠中观察到的子宫胎盘血流减少。我们提议的项目也有潜在的 重要的临床意义；尤其是，我们的研究结果可能确定新的治疗靶点。 或预防宫内发育迟缓。