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

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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.