Regulation of VEGF Expression in Placenta and Membranes

胎盘和胎膜中 VEGF 表达的调节

• 批准号: 6430700
• 负责人: CECILIA CHEUNG
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-21 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6430700
• 关键词: amniotic fluid; embryo /fetus membrane; gene expression; growth factor; hormone regulation /control mechanism; hypoxia; membrane permeability; messenger RNA; placenta; prostaglandin E; prostaglandin endoperoxide synthase; receptor expression; sheep; vascular endothelial growth factors

DESCRIPTION (provided by applicant): A comprehensive understanding of the control of amniotic fluid volume is of major clinical importance. We have identified a vascular pathway within the fetal membranes and fetal surface of the placenta for fluid and solute exchange between the amniotic compartment and fetal blood. This pathway is an important determinant of amniotic fluid volume. Recently, we found expression of vascular endothelial growth factor (VEGF) in the amnion and chorion, and this expression is increased under conditions of enhanced intramembranous absorption. We hypothesize that VEGF is the key regulator of this absorption and factors that stimulate VEGF gene expression in the membranes are important mediators of amniotic fluid volume regulation. In this application, we propose to explore the source and identity of the VEGF stimulatory factors that are activated by blockade of fetal swallowing or fetal hypoxia, conditions that augment intramembranous absorption. The potential factors include PGE2, EGF, TGF, PAP and PDGF derived from the fetal membranes or fetal kidneys. Pregnant sheep will be used as the animal model. In specific aim 1, we propose to determine which factors in the amniotic fluid or fetal urine are induced by fetal esophageal ligation and whether the kidneys or the membranes are the source of the factors. The effect of the factors on VEGF mRNA and protein expression in amnion cells will be examined. Specific aim 2 proposes to investigate the role of PGE2 and growth factors on the hypoxic induction of VEGF gene expression in the fetal membranes. The effect of hypoxia on concentration of these factors in the amniotic fluid and fetal urine will be determined. Whether these factors contribute to the hypoxic induction of VEGF will be tested in amnion cells. In specific aim 3, we propose to examine the regulation of expression and function of the VEGF receptor KDR in amnion cells. The effects of VEGF on KDR mRNA and protein expression in the cells will be explored. The ability of VEGF to stimulate amnion cell proliferation and increase permeability of the amnion/chorin will be delineated. Overall, we will test the hypothesis that augmented intramembranous absorption is caused by up-regulation of VEGF gene expression in the fetal membranes. This is induced by factors in the amniotic fluid that are activated by fetal esophageal ligation or hypoxia. Results from these studies will promote understanding of amniotic fluid volume regulation, and provide important information for diagnosis and management of amniotic fluid disorders in human pregnancy.

描述（由申请人提供）：对项目的全面理解 控制羊水量具有重要的临床意义。我们有 确定了胎膜和胎儿表面内的血管通路 胎盘在羊膜腔和羊膜腔之间进行液体和溶质交换 胎儿的血液。该途径是羊水量的重要决定因素。 最近，我们发现血管内皮生长因子（VEGF）在 羊膜和绒毛膜，并且这种表达在以下条件下增加 增强膜内吸收。我们假设 VEGF 是关键 这种吸收的调节剂和刺激 VEGF 基因表达的因子 羊膜是羊水量调节的重要介质。在 在此应用中，我们建议探索 VEGF 的来源和身份 胎儿吞咽受阻或胎儿受阻而激活的刺激因子 缺氧，增加膜内吸收的条件。潜力 因子包括源自胎膜的 PGE2、EGF、TGF、PAP 和 PDGF 或胎儿肾脏。怀孕的绵羊将被用作动物模型。具体来说 目标1，我们建议确定羊水或胎儿中的哪些因素 尿液是由胎儿食管结扎诱导的，无论是肾脏还是胃 膜是因子的来源。各因素对VEGF mRNA的影响 并将检查羊膜细胞中的蛋白质表达。具体目标2 提出研究 PGE2 和生长因子对缺氧的作用 诱导胎膜中 VEGF 基因的表达。缺氧的影响 羊水和胎儿尿液中这些因子的浓度 决定。这些因素是否有助于VEGF的缺氧诱导 将在羊膜细胞中进行测试。在具体目标 3 中，我们建议审查 羊膜细胞中 VEGF 受体 KDR 表达和功能的调节。 VEGF对细胞内KDR mRNA和蛋白表达的影响 探索过。 VEGF 具有刺激羊膜细胞增殖和 将描绘出羊膜/弦蛋白渗透性的增加。总体而言，我们将 检验膜内吸收增加是由以下因素引起的假设： 胎膜中 VEGF 基因表达上调。这是诱发的 由胎儿食道激活的羊水中的因素 结扎或缺氧。这些研究的结果将促进对 羊水量调节，并提供重要信息 人类妊娠期羊水紊乱的诊断和管理。