Chronic hypoxia, AMPK activation and uterine artery blood flow

慢性缺氧、AMPK 激活与子宫动脉血流

• 批准号: 9925655
• 负责人: Colleen Glyde Julian
• 金额: $ 32.27万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925655
• 关键词: Adenosine Monophosphate; Affect; Agonist; Altitude; Arteries; Biometry; Biopsy; Blood Vessels; Blood flow; Blood specimen; Caliber; Catalytic Domain; Cesarean section; Chronic; DNA Methylation; Data; Discipline of obstetrics; Endothelium; Enzymes; Epigenetic Process; Fetal Growth; Fetal Growth Retardation; Fetal Tissues; Frequencies; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Growth; Homeostasis; House mice; Human; Hypoxia; Infant; Intervention; Ischemia; Link; Measures; Mediating; Metabolic; Metformin; Methylation; Mus; Myometrial; NIH Program Announcements; Peripheral Blood Mononuclear Cell; Pharmacology; Phosphotransferases; Placenta; Plasma; Play; Positioning Attribute; Postpartum Period; Pre-Eclampsia; Pregnancy; Process; Prospective Studies; Protein Isoforms; Protein Kinase; Proteins; Protocols documentation; Public Health; Publications; Regulation; Risk; Role; Sea; Signal Pathway; Signal Transduction; Signaling Protein; Single Nucleotide Polymorphism; Testing; Thoracic aorta; Time; Tissues; Uteroplacental Circulation; Uterus; Vascular Smooth Muscle; Vasodilation; Vasodilator Agents; Weight; Western Blotting; Woman; Work; cohort; drug development; epigenetic regulation; fetal; functional outcomes; health of the mother; human data; improved; in utero; inhibitor/antagonist; innovation; mRNA Expression; mouse model; novel; pregnancy disorder; pregnant; prevent; recruit; residence; response; upstream kinase

Project Summary High altitude residence (HA, >2500 m) increases the frequency of preeclampsia (PreE) and intrauterine growth restriction (IUGR) 3-fold. Since hypoxia is a common cause, HA studies are uniquely positioned to evaluate the mechanistic role of hypoxia, discover new treatments, and alleviate the “almost complete lack of drug development for obstetric indications” noted in PAR-13-389. Adenosine monophosphate kinase (AMPK) is a regulator of metabolic homeostasis that also affects vascular growth and function under hypoxia. We have shown that AMPK plays important roles in the regulation of human uterine artery (UtA) blood flow and fetal growth at HA, and that AMPK activation has vasodilator effects in isolated murine UtA that are potentiated by hypoxia. Our central hypothesis is that AMPK activation promotes vasodilation in the uteroplacental circulation in response to hypoxia to raise UtA blood flow and improve fetal growth at HA. Because hypoxia leads to epigenetic changes that alter the expression of genes regulating of AMPK activity and fetal growth, we propose that DNA methylation influences these AMPK-mediated processes. We present new murine and human data to show that hypoxia a) raises placental phosphorylated (P)- relative to total AMPK levels and the P- as well as the total protein levels of AMPK targets in thoracic aorta and placenta; b) increases the expression of key enzymes activating AMPK in UtA and placenta; and c) alters methylation-expression relationships of AMPK- signaling genes important for fetal growth. We will test our central hypothesis by determining: 1. In Aim 1, the effect of HA pregnancy on AMPK signaling and its relationship to UtA blood flow and fetal growth in humans. We will recruit 102 healthy residents of low altitude (LA, 1600 m, n=53) or HA (3000 m, n=49); measure UtA blood flow and fetal biometry longitudinally; and determine the activation of AMPK, its upstream regulators and downstream targets, the expression levels and DNA methylation of relevant genes in peripheral blood mononuclear cells (PBMCs), and plasma levels of AMPK regulators. 2. In Aim 2, the effects of hypoxia on AMPK activation in human myometrial artery (MA) and placenta, and on MA vasoreactivity. In women participating in Aim 1 who deliver by elective C-section (n=19/altitude), we will obtain myometrial biopsies and placentas to determine a) the activation, expression and DNA methylation status of AMPK, its well-established regulators and downstream targets; b) the effect of HA pregnancy on MA vasoreactivity; and c) whether hypoxia potentiates vasodilator effects of AMPK activation in MA. 3. In Aim 3, the role of AMPK in regulating uteroplacental blood flow and fetal growth in response to hypoxia in mice. Pregnant mice housed at sea level (SL) or HA will be treated with the AMPK activator (AICAR), inhibitor (Compound C), or vehicle (control) for determining the separate and combined effects of hypoxia and AMPK activation on AMPK signaling in UtA, placental and fetal tissues; UtA vascular reactivity and blood flow; and fetal growth.

项目摘要 居住高海拔（HA，> 2500 m）增加了子痫前期（PREE）和宫内生长的自由度 限制（IUGR）3倍。 缺氧的机械作用，发现新疗法并说明“几乎缺乏药物 产科适应症的开发“在13-389杆中指出。腺苷一磷酸激酶（AMPK）是一个 代谢稳态的调节剂也会影响我们患有缺氧的血管生长和功能。 表明AMPK在人子宫动脉（UTA）血流和胎儿的调节中起重要作用 HA的增长，AMPK AMPK激活在孤立的鼠UTA中具有血管扩张剂的作用 缺氧。 响应缺氧的雷斯uta血流并改善了HA的胎儿生长。 表观遗传变化改变了调节AMPK AMPK和胎儿生长的基因的表达，我们提出 DNA甲基化影响了这些AMPK介导的过程。 表明缺氧a）脱落胎盘磷酸化（p） - 与总AMPK水平以及P -as as和 胸主动脉和胎盘中AMPK靶标的总蛋白质水平； 在UTA和胎盘中激活AMPK的酶； 信号基因对胎儿生长很重要。 1。在AIM 1中，HA妊娠对AMPK信号传导及其与UTA血液胎儿的关系 人类的增长。 n = 49）; 上游调节剂和下游靶标，相关的表达水平和DNA甲基化 外周血单核细胞中的基因（PBMC）和AMPK调节剂的血浆水平。 2。在AIM 2中，缺氧对人肌层动脉（MA）和胎盘的AMPK激活的影响以及对 通过EALTIVE C剖面（n = 19/高度）参加AIM 1的女性血管反应性。 获得肌层活检和胎盘以确定A）激活，表达和DNA甲基化 AMPK的地位，其成熟的监管机构和下游目标； MA血管反应性； 3。在AIM 3中，AMPK在调节子宫牙科血流和胎儿呼吸中的作用 在海平面（SL）或HA的小鼠中 抑制剂（Compound C）或用于确定缺氧的单独和组合作用的媒介物（对照） AMPK激活UTA，胎盘和胎儿组织中的AMPK信号； 血流和胎儿生长。