PPARy and Uterine Vascular Dysfunction in Diabetic Pregnancy

PPARy 与糖尿病妊娠期间的子宫血管功能障碍

基本信息

批准号：
7678544
负责人：
NATALIA I GOKINA
金额：
$ 33.86万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7678544
关键词：
Acute Arteries Blood Circulation Blood Glucose Blood Vessels Blood flow Bradykinin Calcium-Activated Potassium Channel Caliber Cyclic GMP Data Development Diabetes Mellitus Diacylglycerol Kinase Dilatation - action Disease Down-Regulation Effectiveness Endothelial Cells Experimental Diabetes Mellitus Female of child bearing age Fetoplacental Circulation Fetus Functional disorder Generations Glucose Goals Growth Hour Hyperglycemia Hypertension Impairment Ion Channel Ions Knowledge Link Measurement Mediating Membrane Potentials Modeling Molecular Morbidity - disease rate Nitric Oxide Nutrient Obesity Oxidative Stress Oxygen PPAR gamma Perinatal Phlorhizin Physiological Placenta Potassium Channel Pre-Eclampsia Pregnancy Pregnancy Outcome Pregnancy Tests Pregnancy in Diabetics Process Production Radial Rattus Regulation Relative (related person)Resistance Role Signal Transduction Smooth Muscle Smooth Muscle Myocytes Superoxides System Up-Regulation Vascular blood supply Vascular resistance Vasodilation Vasodilator Agents Woman base diabetic diabetic rat fetus hypoxia high risk improved inhibitor/antagonist insight insulin sensitizing drugs medical complication mortality novel pregnant pressure prevent public health relevance receptor research study response

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus is one of the most common medical complications of pregnancy that significantly contributes to maternal and perinatal morbidity and mortality. Women with pregnancies complicated by diabetes are also at a higher risk for the development of hypertension and preeclampsia. A decreased uteroplacental blood flow in diabetic pregnancy suggests an abnormal uterine artery structural or/and functional adaptation causing placental and fetal hypoxia and increased rates of hypertension in pregnancy and preeclampsia. The long-term goal of this proposal is to understand the causes and cellular and molecular mechanisms underlying uteroplacental endothelial dysfunction induced by diabetic pregnancy, with a specific focus on the role of hyperglycemia, PKC and peroxisome proliferator-activated receptor gamma (PPARg) in this process. Our central hypothesis is that diabetes in pregnancy causes endothelial dysfunction of uteroplacental arteries manifested by decreased NO- and EDHF-mediated vasodilation. Hyperglycemia-induced PKC activation results in impairment of Ca2+ signaling leading to decreased production of NO and diminished stimulation of Ca2+-activated potassium channels (SKCa and IKCa) (Specific Aim 1). PKC-specific inhibition of SKCa and IKCa channels is an additional novel mechanism of impaired EDHF-mediated vasodilation in diabetes (Specific Aim 2). Hyperglycemia-induced superoxide production up-regulates PDE expression resulting in reduction of NO- cGMP-PKG signaling and development of nitric oxide resistance in diabetic pregnancy (Specific Aim 3). Direct beneficial effects of PPARg on arterial function in diabetic pregnancy results from moderation in DAG-PKC activity and is mediated by inhibition of superoxide production and up-regulation of DAG-kinase. Furthermore, we propose that hyperglycemia-PKC down-regulates PPARg expression contributing to diabetes-induced impairment of cellular and molecular mechanisms responsible for maternal uterine adaptation in pregnancy (Specific Aim 4). We propose to use a rat model of STZ-induced diabetes to explore the effects of hyperglycemia in uteroplacental vascular dysfunction in pregnancy. We will focus on a specific part of the maternal uterine vasculature - small radial uterine arteries - that regulate the blood supply to the placenta and fetus. The four Specific aims will integrate physiological function (regulation of arterial diameter) with intracellular mechanisms (Ca2+ signaling and ion channel function) and will be accomplished by direct measurements of arterial diameter, intracellular Ca2+ and NO, membrane potential, expression and distribution of PKC and PDE, and ion currents in single endothelial and smooth muscle cells. PUBLIC HEALTH RELEVANCE: The proposed studies will provide new insights into the role of hyperglycemia, PKC and PPARg in diabetes- induced modulation of intracellular molecular mechanisms regulating uteroplacental vascular function and significantly improve our knowledge of the mechanisms underlying abnormal maternal uterine circulation in pregnancies complicated by diabetes.

描述（由申请人提供）：糖尿病是妊娠期最常见的医学并发症之一，显着增加孕产妇和围产期的发病率和死亡率。妊娠合并糖尿病的女性患高血压和先兆子痫的风险也较高。糖尿病妊娠期间子宫胎盘血流量减少表明子宫动脉结构或/和功能适应异常，导致胎盘和胎儿缺氧以及妊娠期高血压和先兆子痫的发生率增加。该提案的长期目标是了解糖尿病妊娠引起的子宫胎盘内皮功能障碍的原因以及细胞和分子机制，特别关注高血糖、PKC 和过氧化物酶体增殖物激活受体 γ (PPARg) 在此过程中的作用。过程。我们的中心假设是妊娠期糖尿病会导致子宫胎盘动脉内皮功能障碍，表现为 NO 和 EDHF 介导的血管舒张功能减少。高血糖诱导的 PKC 激活导致 Ca2+ 信号传导受损，从而导致 NO 产生减少，并减少 Ca2+ 激活钾通道（SKCa 和 IKCa）的刺激（具体目标 1）。 SKCa 和 IKCa 通道的 PKC 特异性抑制是糖尿病中 EDHF 介导的血管舒张受损的另一种新机制（具体目标 2）。高血糖诱导的超氧化物产生上调 PDE 表达，导致糖尿病妊娠期间 NO-cGMP-PKG 信号传导减少和一氧化氮抵抗的发展（具体目标 3）。 PPARg 对妊娠糖尿病患者动脉功能的直接有益作用是由于 DAG-PKC 活性的调节而产生的，并且是通过抑制超氧化物产生和上调 DAG 激酶介导的。此外，我们提出高血糖-PKC 下调 PPARg 表达，导致糖尿病引起的妊娠期母体子宫适应的细胞和分子机制受损（具体目标 4）。我们建议使用STZ诱导的糖尿病大鼠模型来探讨高血糖对妊娠期子宫胎盘血管功能障碍的影响。我们将重点关注母体子宫脉管系统的特定部分 - 子宫桡动脉 - 调节胎盘和胎儿的血液供应。四个具体目标将生理功能（动脉直径的调节）与细胞内机制（Ca2+信号传导和离子通道功能）结合起来，并将通过直接测量动脉直径、细胞内Ca2+和NO、膜电位、PKC和PKC的表达和分布来实现。 PDE 以及单个内皮细胞和平滑肌细胞中的离子电流。公共健康相关性：拟议的研究将为高血糖、PKC 和 PPARg 在糖尿病诱导的调节子宫胎盘血管功能的细胞内分子机制的调节中的作用提供新的见解，并显着提高我们对妊娠期母体子宫循环异常的机制的认识。糖尿病。