Regulation of VEGF Expression in Placenta and Membranes

描述(由申请人提供)：全面了解 羊水量的控制具有重要的临床意义。我们有 在胎膜和胎儿表面发现了一条血管通路 羊膜室和胎盘之间液体和溶质交换的胎盘 胎儿的血。这一途径是决定羊水量的重要因素。 最近，我们发现血管内皮细胞生长因子(VEGF)在血管内皮细胞中的表达。 羊膜和绒毛膜，这种表达在以下条件下增加 膜内吸收增强。我们假设血管内皮生长因子是关键 血管内皮细胞这种吸收的调节因子及其促进血管内皮生长因子的表达 羊水膜是调节羊水容量的重要介质。在……里面 在这一应用中，我们建议探索血管内皮生长因子的来源和身份 因阻断胎儿吞咽或胎儿而激活的刺激因子 缺氧，增加膜内吸收的条件。潜力 因子包括胎膜来源的前列腺素E_2、表皮生长因子、转化生长因子、PAP和血小板衍生生长因子 或者是胎儿肾脏。怀孕的绵羊将被用作动物模型。具体而言 目的1，我们建议确定羊水或胎儿中的哪些因素 尿液是由胎儿食道结扎引起的，无论是肾脏还是 膜是这些因素的来源。影响血管内皮细胞生长因子基因表达的因素 并将检测羊膜细胞中的蛋白质表达。具体目标2 建议研究前列腺素E_2和生长因子在低氧中的作用 血管内皮生长因子基因在胎膜中的诱导表达。低氧的影响 这些因素在羊水和胎儿尿液中的浓度将 下定决心。这些因素是否参与了低氧诱导的血管内皮生长因子 将在羊膜细胞中进行测试。在具体目标3中，我们建议研究 羊膜细胞中血管内皮生长因子受体KDR的表达和功能调节 血管内皮细胞生长因子对KDR基因和蛋白表达的影响 探索过了。血管内皮生长因子刺激羊膜细胞增殖的能力 增加羊膜/Chorin的渗透性将被勾画出来。总的来说，我们将 检验膜内吸收增强是由以下因素引起的假设 胎膜中血管内皮生长因子基因表达上调。这是诱导的 由胎儿食道激活的羊水中的因子 结扎或缺氧。这些研究的结果将促进对 羊水量调节，为临床提供重要信息。 妊娠合并羊水紊乱的诊断与处理。

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.