Mediators of impaired fetoplacental angiogenesis in fetal growth restriction

描述（由申请人提供）：继发于胎盘功能障碍的胎儿生长受限是围产期发病率和死亡率的主要原因。具体来说，这些妊娠中胎儿胎盘血管阻力异常升高（FGRadv），如脐动脉多普勒速度异常所反映的，是一个不祥的发现，它会大大增加不良围产期结局、神经发育后果和长期健康问题的风险。相比之下，保留胎胎盘血流的生长受限妊娠的围产期结局与正常生长的妊娠相似。这表明FGR胎儿的胎胎盘循环中的血流受损在影响胎儿健康和结局方面起着重要作用。目前，除了给药外，尚无预防或治疗FGRadv的措施，临床数据表明，这种干预措施不会影响总生存期或长期预后。因此，了解导致FGRadv的机制是至关重要的，如果我们要确定可以保护或恢复胎儿胎盘血流和改善围产期结局的潜在靶点。在FGRadv中一直可见的一个主要胎盘异常是胎儿胎盘血管缺乏足够的分支血管生成。在正常妊娠中，分支和非分支血管生成持续整个妊娠后半期，这使得胎盘血管阻力适当降低，并随着妊娠的进展而继续。该建议的总体目标是确定FGRadv中不适当的胎胎盘血管生成的分子机制。我们假设FGRadv胎盘的内皮导致内皮细胞（EC）运动性和EC-EC粘附性受损。我们进一步假设这是由芳烃受体核转运子(ARNT，也称为缺氧诱导因子1- β [HIF1？])，导致血管内皮生长因子A （VEGFA）信号的下调。我们的具体目标如下：(1)表征FGRadv中损害EC功能和血管生成的功能性内皮细胞特异性缺陷；(2)确定ARNT调控胎胎盘血管生成的机制；(3)建立影响正常EC功能和胎盘血管生成的VEGFA信号缺陷。完成这些目标将确定异常胎胎盘血管生成发生的主要机制途径，并对胎儿的围产期和长期结局产生不利影响。

DESCRIPTION (provided by applicant): Fetal growth restriction secondary to placental dysfunction is a major cause of perinatal morbidity and mortality. Specifically, abnormally elevated fetoplacental vascular resistance in these pregnancies (FGRadv), as reflected by abnormal umbilical artery Doppler velocimetry, is an ominous finding that substantially increases risk for adverse perinatal outcome, neurodevelopmental consequences, and long-term health problems. In contrast, growth-restricted pregnancies with preserved fetoplacental blood flow demonstrate perinatal outcomes similar to those with normal growth. This suggests that impaired blood flow within the fetoplacental circulation in FGR fetuses plays a major role in compromising fetal well-being and outcome. Currently, no preventive or therapeutic measures for FGRadv exist other than delivery, and clinical data demonstrate that this intervention does not impact overall survival or long-term outcome. Thus, understanding the mechanisms that result in FGRadv is crucial if we are to identify potential targets that can protect or restore fetoplacental blood flow and improve perinatal outcomes. One major placental abnormality that is consistently seen in FGRadv is a lack of adequate branching angiogenesis of the fetoplacental vasculature. In normal pregnancies, branching and non-branching angiogenesis persists throughout the second half of pregnancy, which allows for an appropriate decrement in placental vascular resistance that continues as gestation progresses. The overall objective of this proposal is to determine the molecular mechanisms by which improper fetoplacental angiogenesis occurs in FGRadv. We hypothesize that endothelium of FGRadv placentas result in impaired endothelial cell (EC) motility and EC-EC adherence. We further hypothesize that this is mediated by aryl hydrocarbon receptor nuclear translocator (ARNT; also known as hypoxia inducible factor 1-beta [HIF1?]), which results in down-regulation of vascular endothelial growth factor A (VEGFA) signaling. Our specific aims are as follows: (1) To characterize the functional endothelial cell-specific defect that impairs EC function and angiogenesis in FGRadv; (2) To determine the mechanism(s) by which ARNT regulates fetoplacental angiogenesis; (3) To establish the VEGFA signaling defects that impair proper EC function and fetoplacental angiogenesis. Completion of these aims will identify a major mechanistic pathway by which aberrant fetoplacental angiogenesis occurs and adversely impacts perinatal and long-term outcome of the fetus.