Placental Insufficiency in Transgenic Mouse Model of Preeclampsia and IUGR

描述(申请人提供)：妊娠高血压综合征(先兆子痫、毒血症)和胎儿生长受限(IUGR)是常见的和威胁生命的妊娠并发症。目前，没有有效的筛查测试，除了早产外，也没有有效的治疗方法。子痫前期和胎儿宫内发育迟缓有着非常相似的子宫胎盘病理。他们的胎盘通常生长受限，他们有胎盘梗塞，切片显示异常的胎盘结构。多普勒超声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征兆。此外，子痫前期和/或宫内发育迟缓的妇女在这些疾病的临床表现前几个月就表现出胎盘S-Flt1(血管内皮生长因子受体)的上调，这是相对缺血的迹象。这些观察表明，子宫胎盘血流异常可能在子痫前期和胎儿宫内发育迟缓中起关键作用。为了验证这一假设，我们验证了一个基因工程小鼠模型，该模型模拟了一种常见的人类血管紧张素原(AGT)变体，该变体与先兆子痫和IUGR有关。这种“生理学”的小鼠模型在怀孕期间不能增加其血容量，类似于患有先兆子痫的女性。它还显示子宫胎盘功能不全的多种特征，如胎儿生长受限、脐带多普勒舒张期血流消失和sFlt-1升高。在我们的模型中，我们建议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婴结局。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偶联基因递送系统来特异性地增加子宫-胎盘界面的VEGF表达。这些实验将使我们能够测试在我们的模型中与正常对照组相比，血管内皮生长因子水平、子宫胎盘血流和妊娠结局之间的关系。总而言之，我们的新方法使用了基因工程小鼠模型和创新的微泡技术来测量子宫胎盘血流，并直接将治疗输送到胎盘。我们的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，并是未来研究分子机制和潜在应用于女性的第一步。

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.