ET and PAF Synergism in intrauterine growth restriction

ET 和 PAF 在宫内生长受限中的协同作用

• 批准号: 6731595
• 负责人: LARRY G THAETE
• 金额: $ 22.12万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731595
• 关键词: clinical research; endometrium; endothelin; female; gene expression; human subject; immunocytochemistry; ischemia; laboratory rat; oxidative stress; pathologic process; platelet activating factor; prenatal growth disorder; reproductive system circulation; tissue /cell culture; uterus; women' s health

DESCRIPTION (provided by applicant): Intrauterine growth restriction (IUGR) complicates 4 to 7% of all pregnancies in developed countries, and is a major contributor to perinatal morbidity and mortality. Inadequate uteroplacental perfusion is fundamental to the majority of cases of IUGR in humans. Both faulty trophoblastic invasion of the maternal spiral arteries as well as vasoconstriction of the maternal vasculature may contribute to suboptimal uteroplacental perfusion. Faulty trophoblastic invasion, however, does not fully account for decreased uteroplacental perfusion and consequent IUGR because placental perfusion and fetal growth may be normal where faulty trophoblastic invasion is observed. Further, not all cases of IUGR associated with decreased uteroplacental perfusion have histologic evidence of faulty trophoblastic invasion. Vasoconstriction of the maternal vasculature contributes to the decreased uteroplacental perfusion commonly observed in cases of IUGR. Suboptimal placental perfusion (i.e. ischemia) results in the release of vascular mediators that may further compromise placental perfusion. The contribution of vasoactive mediators to the decreased uteroplacental perfusion commonly observed in human IUGR is not known. The recently developed uterine ischemia/reperfusion (I/R) model of IUGR in the rat is uniquely suited to study the contribution of vascular mediators to decreased uteroplacental perfusion. Temporary uterine ischemia in one of the two horns of the gravid rat uterus results in IUGR not just in one but in both horns, presumably as a result &circulating mediators. Endothelin-I (ET-1), a locally active vasoconstrictor, contributes to the regulation of uterine and placental vascular tone. We hypothesize that ET-1 plays a primary role in the pathophysiology of fetal growth restriction. Ischemia is a potent stimulus to ET-1 production, and ET-1 is up-regulated in IUGR both in humans and in animals. Beyond its direct vasoconstrictive effects, ET-1 also upregulates the production of platelet activating factor (PAF), a potent vasoactive and inflammatory mediator. ET-1 and PAF may act synergistically to decrease local perfusion. Therefore, we will evaluate the contribution of these two key mediators to the pathophysiology of I/R-induced IUGR. We have previously demonstrated that ET-I plays a primary role in two other models of IUGR. We now propose to evaluate the synergistic role of endogenous ET-1 and PAF in ischemia-induced IUGR, and to investigate the molecular mechanisms regulating their activities. Our goal is to assess the specific role of ET-1, as well as its interaction with PAF, in the pathophysiology of I/R-induced IUGR.

描述（由申请人提供）：宫内生长受限 (IUGR) 使发达国家 4% 至 7% 的妊娠变得复杂，并且是围产期发病率和死亡率的主要原因。子宫胎盘灌注不足是大多数人类 IUGR 病例的根本原因。母体螺旋动脉的错误滋养层侵袭以及母体脉管系统的血管收缩都可能导致子宫胎盘灌注不理想。然而，错误的滋养细胞侵袭并不能完全解释子宫胎盘灌注减少和随后的 IUGR，因为在观察到错误的滋养细胞侵袭时胎盘灌注和胎儿生长可能是正常的。此外，并非所有与子宫胎盘灌注减少相关的 IUGR 病例都有滋养细胞侵袭错误的组织学证据。 母体脉管系统的血管收缩导致子宫胎盘灌注减少，这在 IUGR 病例中常见。胎盘灌注不理想（即缺血）会导致血管介质的释放，从而可能进一步损害胎盘灌注。血管活性介质对人类 IUGR 中常见的子宫胎盘灌注减少的影响尚不清楚。最近开发的大鼠 IUGR 子宫缺血/再灌注 (I/R) 模型特别适合研究血管介质对子宫胎盘灌注减少的影响。妊娠大鼠子宫两个角之一的暂时性子宫缺血不仅导致一侧子宫角出现 IUGR，而且还导致两个角出现 IUGR，这可能是循环介质的结果。内皮素-I (ET-1) 是一种局部活性血管收缩剂，有助于调节子宫和胎盘血管张力。我们假设 ET-1 在胎儿生长受限的病理生理学中起主要作用。缺血是 ET-1 产生的有力刺激因素，在人类和动物的 IUGR 中 ET-1 均上调。除了直接的血管收缩作用外，ET-1 还能上调血小板活化因子 (PAF) 的产生，血小板活化因子是一种有效的血管活性和炎症介质。 ET-1 和 PAF 可能协同作用以减少局部灌注。因此，我们将评估这两个关键介质对 I/R 诱导的 IUGR 病理生理学的贡献。我们之前已经证明 ET-I 在另外两种 IUGR 模型中发挥主要作用。我们现在建议评估内源性 ET-1 和 PAF 在缺血诱导的 IUGR 中的协同作用，并研究调节其活性的分子机制。我们的目标是评估 ET-1 的具体作用及其与 PAF 的相互作用，在 I/R 诱导的 IUGR 的病理生理学中。