Role of Placental Insufficiency in Preeclampsia, IUGR, and Fetal Programming of H

描述（由申请人提供）：妊娠高血压（先兆子痫、毒血症）和胎儿生长受限（IUGR）是常见的危及生命的妊娠并发症。目前，没有有效的筛查测试，也没有有效的治疗方法，除了早期分娩的婴儿。 先兆子痫和IUGR具有非常相似的子宫胎盘病理学。他们的胎盘通常生长受限，有胎盘梗死，切片显示胎盘结构异常。多普勒超声常显示胎儿脐带舒张末期血流缺失，这是子宫胎盘功能不全的间接征象。此外，患有先兆子痫和/或IUGR的女性在这些疾病的临床表现前数月表现出胎盘s-flt 1（血管内皮生长因子[VEGF]受体）的上调，这是相对缺血的迹象。这些观察结果表明，子宫胎盘血流异常可能在先兆子痫和IUGR中起关键作用。 为了验证这一假设，我们验证了一种基因工程小鼠模型，该模型模拟了与先兆子痫和IUGR相关的常见人类血管紧张素原（AGT）变体。这种“生理”小鼠模型在怀孕期间未能增加其血容量，类似于患有先兆子痫的妇女。它还显示了子宫胎盘功能不全的多种特征，如胎儿生长受限、脐带多普勒显示舒张期血流缺失和sflt-1升高。 我们建议使用一种新的定量微泡增强成像系统，在我们的模型中，将子宫胎盘血流与母体和胎儿的结局相关联。此外，为了更好地了解VEGF和sflt-1在胎盘功能不全的病理生理学中的作用，我们将使用我们的微泡缀合基因递送系统来特异性地增加子宫胎盘界面处的VEGF表达。这些实验将使我们能够测试与正常对照相比，我们模型中VEGF水平，子宫胎盘血流和妊娠结局之间的关系。 总之，我们的新方法使用基因工程小鼠模型和创新的新型微泡技术来测量子宫胎盘血流并直接向胎盘提供治疗。我们的研究结果将帮助我们更好地了解这些严重人类疾病的潜在病理学，并且是未来研究女性分子机制和潜在应用的第一步。 公共卫生相关性：先兆子痫和胎儿生长受限是常见的和危及生命的妊娠并发症，它们经常一起发生，并且可能具有共同的潜在病理生理学。目前，没有有效的测试来确定哪些怀孕有患这些疾病的风险，除了提前分娩婴儿之外，没有有效的治疗方法。我们的新方法使用基因工程小鼠模型和创新的新微泡技术来测试子宫胎盘血流异常是否可能是这些疾病的根本原因，以及子宫螺旋动脉中VEGF表达的增加是否会改善或加重病情。

DESCRIPTION (provided by applicant): Pregnancy-induced hypertension (preeclampsia, toxemia) and fetal growth restriction (IUGR) are common and life-threatening complications of pregnancy. Currently, there are no effective screening tests and there are no effective treatments other than early delivery of the baby. Preeclampsia and IUGR share very similar uteroplacental pathology. Their placentas are often growth restricted, they have placental infarctions, and sections reveal abnormal placental architectural. Doppler ultrasound often reveals absent end-diastolic flow in the fetal umbilical cord, which is an indirect sign of uteroplacental insufficiency. Moreover, women with preeclampsia and/or IUGR demonstrate upregulation of placental s-flt1 (vascular endothelial growth factor [VEGF] receptor), a sign of relative ischemia, and months before the clinical presentation of these diseases. These observations suggest that abnormal uteroplacental blood flow may play a key role in preeclampsia and IUGR. To test this hypothesis, we validated a genetically engineered mouse model that simulates a common human angiotensinogen (AGT) variant that is associated with preeclampsia and IUGR. This "physiologic" mouse model fails to increase its blood volume during pregnancy, similar to women with preeclampsia. It also demonstrates multiple features of uteroplacental insufficiency such as fetal growth restriction, absent diastolic flow by cord Doppler, and elevated sflt-1. We propose to use a novel quantitative microbubble-enhanced imaging system to correlate uteroplacental blood flow in vivo with maternal and fetal outcomes in our model. In addition, to better understand the role of VEGF and sflt-1 in the pathophysiology of placental insufficiency, we will employ our microbubble-conjugated gene delivery system to specifically increase VEGF expression at the uteroplacental interface. These experiments will allow us to test for a relationship between VEGF levels, uteroplacental blood flow, and pregnancy outcomes in our model compared to normal controls. In summary, our novel approach uses a genetically engineered mouse model and an innovative new microbubble technology to measure uteroplacental blood flow and directly deliver treatment to the placenta. Our results will help us better understand the underlying pathology of these serious human diseases and are the first steps toward future studies investigating molecular mechanisms and potential applications in women. PUBLIC HEALTH RELEVANCE: Preeclampsia and fetal growth restriction are common and life-threatening complications of pregnancy, which often occur together and likely share a common underlying pathophysiology. Currently, there are no effective tests to determine which pregnancies are at risk for these diseases, and there are no effective treatments other than early delivery of the baby. Our novel approach uses a genetically engineered mouse model and an innovative new microbubble technology to test whether abnormal uteroplacental blood flow may be an underlying cause of these diseases and whether increasing VEGF expression in uterine spiral arteries ameliorates or exacerbates the condition.