Placental Insufficiency in Transgenic Mouse Model of Preeclampsia and IUGR

描述（由申请人提供）：妊娠高血压（子痫前期、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，只能提前分娩。子痫前期和IUGR具有非常相似的子宫-胎盘病理。他们的胎盘通常生长受限，有胎盘梗死，切片显示异常的胎盘结构。多普勒超声经常显示胎儿脐带舒张末血流缺失，这是子宫胎盘功能不全的间接迹象。此外，患有先兆子痫和/或IUGR的妇女在出现这些疾病的临床表现前几个月就表现出胎盘s-flt1（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，异常子宫胎盘血流可能在子痫前期和IUGR中起关键作用。为了验证这一假设，我们验证了一个基因工程小鼠模型，该模型模拟了与子痫前期和IUGR相关的常见人类血管紧张素原（AGT）变异。这种“生理性”小鼠模型在怀孕期间无法增加其血容量，这与患有先兆子痫的女性相似。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，脐带多普勒无舒张期血流，sflt-1升高。我们建议在我们的模型中使用一种新的定量微泡增强成像系统来关联体内子宫胎盘血流与母体和胎儿结局。此外，为了更好地了解VEGF和sflt-1在胎盘功能不全病理生理中的作用，我们将利用我们的微泡结合基因传递系统特异性地增加子宫-胎盘界面VEGF的表达。这些实验将使我们能够在我们的模型中与正常对照组比较，测试VEGF水平、子宫胎盘血流和妊娠结局之间的关系。总之，我们的新方法使用了一种基因工程小鼠模型和一种创新的新微泡技术来测量子宫胎盘血流并直接向胎盘输送治疗。我们的研究结果将帮助我们更好地理解这些严重人类疾病的潜在病理，是未来研究分子机制和女性潜在应用的第一步。

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.