Mediators of impaired fetoplacental angiogenesis in fetal growth restriction

胎儿生长受限中胎儿胎盘血管生成受损的介质

• 批准号: 8759305
• 负责人: EMILY J SU
• 金额: $ 38.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-02-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759305
• 关键词: ARNT gene; ARNT protein; Adherence; Biological Assay; Blood Vessels; Blood flow; Cell Death; Cell physiology; Chemotaxis; Clinical; Clinical Data; Cytoskeleton; Data; Defect; Development; Doppler velocimetry; Down-Regulation; Endothelial Cells; Endothelium; Event; Fetal Growth; Fetal Growth Retardation; Fetoplacental Circulation; Fetus; Functional disorder; Gene Targeting; Genes; Genetic Transcription; Gestational Age; Goals; Growth; Health; Hypoxia; In Vitro; Incidence; Intervention; Knowledge; Maintenance; Measures; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Neonatal; Nuclear Receptors; Outcome; Pathway interactions; Perinatal; Personal Satisfaction; Physiological; Placenta; Play; Pregnancy; Preventive; Proteins; Repression; Research; Research Project Grants; Risk; Role; Secondary to; Signal Transduction; Structure of umbilical artery; Testing; Therapeutic; Trees; Tube; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular resistance; Villous; angiogenesis; cadherin 5; cell motility; fetal; functional mimics; human ARNT protein; hypoxia inducible factor 1; improved; in utero; in vivo; knock-down; mortality; overexpression; public health relevance; stillbirth; vascular bed

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.

描述（由申请人提供）：胎盘功能障碍继发的胎儿生长受限是围产期发病率和死亡率的主要原因。具体而言，异常升高的胎儿胎盘血管阻力在这些怀孕（FGRadv），反映了异常的脐动脉多普勒测速，是一个不祥的发现，大大增加了风险的不良围产期结局，神经发育的后果，和长期的健康问题。相反，胎儿胎盘血流保留的生长受限妊娠显示出与正常生长妊娠相似的围产期结局。这表明FGR胎儿中胎儿胎盘循环内的血流受损在损害胎儿健康和结局中起主要作用。目前，除递送外，不存在FGRadv的预防或治疗措施，临床数据表明这种干预不影响总生存率或长期结局。因此，如果我们要确定可以保护或恢复胎儿胎盘血流并改善围产期结局的潜在靶点，那么了解导致FGRadv的机制至关重要。在FGRadv中持续观察到的一个主要胎盘异常是胎儿胎盘血管系统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在整个妊娠的后半期持续存在，这使得胎盘血管阻力随着妊娠的进展而适当降低。该建议的总体目标是确定FGRadv中胎儿胎盘血管生成不当的分子机制。我们推测FGRadv胎盘的内皮导致内皮细胞（EC）运动和EC-EC粘附受损。我们进一步假设，这是由芳香烃受体核转运蛋白（ARNT;也称为缺氧诱导因子1-β [HIF 1？]）介导的，其导致血管内皮生长因子A（VEGFA）信号转导的下调。我们的具体目标如下：（1）表征功能性内皮细胞特异性缺陷，其损害FGRadv中的EC功能和血管生成;（2）确定ARNT调节胎儿胎盘血管生成的机制;（3）建立损害适当EC功能和胎儿胎盘血管生成的VEGFA信号传导缺陷。这些目标的完成将确定一个主要的机制途径，异常胎儿胎盘血管生成的发生和不利影响围产期和长期的结果胎儿。