Long-Term Hypoxemia and Uterine Vascular Adaptation to Pregnancy

长期低氧血症与子宫血管对妊娠的适应

基本信息

批准号：
8327781
负责人：
Lubo Zhang
金额：
$ 21.48万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8327781
关键词：
Acclimatization Actins Address Adult Adverse effects Altitude Animals Arteries Attenuated Biochemical Biological Models Blood Circulation Blood Vessels Blood flow Cardiovascular Diseases Cardiovascular system Chronic Development Down-Regulation Employee Strikes Enzymes Estrogen Receptors Estrogens Fetal Development Fetal Growth Retardation Fetus Gene Expression Genomics Goals Growth Hypoxemia Hypoxia Isoenzymes Lead Mediating Mitogen-Activated Protein Kinases Molecular Mothers Nitric Oxide Organ Personal Satisfaction Physiological Physiological Adaptation Pre-Eclampsia Pregnancy Progesterone Progesterone Receptors Protein Kinase C Risk Role Sea Series Sheep Signal Pathway Steroids Systems Development Testing Up-Regulation Uteroplacental Circulation clinically significant enzyme activity fetal improved in vivo insight novel polymerization pregnant pressure receptor research study response steroid hormone tissue culture

项目摘要

The long-term goal of the project is to understand the mechanisms underlying the adverse effect of chronic hypoxia on uterine blood flow in pregnancy. Chronic hypoxia during the course of pregnancy is one of the most common insults to the maternal cardiovascular system and fetal development, and is associated with an increased risk of preeclampsia and fetal intrauterine growth restriction. Previous studies have demonstrated that hypoxia has profound effects on uterine vascular reactivity and inhibits pregnancyinduced adaptation of uterine artery contractility. Although molecular mechanisms remain poorty understood, recent studies have suggested genomic mechanisms of the steroid hormones, estrogen and progesterone in regulating pressure-dependent myogenic tone of the uterine artery in adaptation to pregnancy. Pressure-dependent myogenic contraction is an important physiological mechanism that regulates basal vascular tone and contributes significanfiy to the modulafion of organ blood flow. The preliminary studies demonstrated that long-term high altitude hypoxia during pregnancy significantly increased the myogenic reactivity in the uterine artery of pregnant sheep and eliminated the differences in pressure-induced myogenic tone in uterine arteries between nonpregnant and pregnant animals. The proposed studies will focus on the mechanisms and test the main hypothesis that chronic hypoxia inhibits the steroid hormones (estrogen and progesterone)-mediated adaptation of ERK1/2 and PKC signaling pathways, resulting in increased myogenic tone of the uterine artery in pregnancy. To test this hypothesis, three Specific Aims are proposed to determine whether and to what extent long-term high altitude hypoxia during pregnancy 1) inhibits steroids-mediated upregulation of ERK1/2 gene expression and downregulafion of the PKC activity in the uterine artery, 2) inhibits steroids-mediated downregulation of pressure-dependent myogenic tone in the uterine artery, and 3) whether chronic hypoxia has direct effects on the steroids-mediated responses in the uterine arteries. The results will provide exciting novel insights in biochemical, molecular, cellular, and pathophysiological adaptafion mechanisms involved in altering uteroplacental circulation in response to hypoxia in pregnancy, which has obvious clinical significance because the maladaptation of uterine circulation caused by chronic hypoxia in pregnancy is associated with fetal developmental abnormalities and maternal cardiovascular disorders.

该项目的长期目标是了解慢性不良影响的基础机制妊娠子宫血流缺氧。怀孕期间的慢性缺氧是对母体心血管系统和胎儿发育的最常见侮辱，并且是相关的随着子痫前期和胎儿内生长限制的风险增加。先前的研究已有证明缺氧对子宫血管反应性有深远的影响，并抑制了妊娠诱导的子宫动脉收缩性的适应。尽管分子机制保持贫困理解，最近的研究表明了类固醇激素，雌激素和孕酮在调节子宫动脉的压力依赖性肌张力中以适应怀孕。压力依赖性的肌源性收缩是一种重要的生理机制调节基底血管张力，并为器官血流的模拟贡献显着。这初步研究表明，怀孕期间长期高海拔缺氧提高了怀孕绵羊的子宫动脉的肌原反应性，并消除了压力诱导的非怀孕动物和怀孕动物之间的子宫动脉肌张力张力。这拟议的研究将重点介绍机制，并检验慢性缺氧抑制的主要假设类固醇激素（雌激素和孕激素）介导的ERK1/2和PKC信号的适应途径，导致妊娠子宫动脉的肌源性增加。为了检验这一假设，提出了三个具体目标，以确定是否以及在多大程度上长期高海拔缺氧怀孕期间1）抑制类固醇介导的ERK1/2基因表达和子宫动脉中PKC活性的下调，2）抑制类固醇介导的下调子宫动脉中依赖压力依赖性肌张力，3）慢性缺氧是否具有直接影响在类固醇介导的子宫动脉中的反应上。结果将提供令人兴奋的新颖见解在生化，分子，细胞和病理生理适应性机制中对怀孕中缺氧的响应子宫循环，这具有明显的临床意义因为妊娠慢性缺氧引起的子宫循环的不良适应与胎儿发育异常和母体心血管疾病。