Preeclampsia (PE), a disease caused by vascular disorders in the placenta, affects 3-7% of pregnancies, resulting in increased neonatal and maternal morbidity and mortality. PE is responsible for 15% of preterm births and is the second largest cause of maternal mortality worldwide. Consequences of PE include maternal hypertension and renal dysfunction, fetal growth restriction, preterm birth, and even perinatal death. Mothers and offspring who have survived a PE pregnancy, have increased risk for long-term cardiovascular disease. NOTCH protein expression is altered in PE placentas and Notch2 deletion in mouse trophoblasts results in poor placental perfusion, a characteristic of PE. Thus, Notch is implicated in the pathogenesis of PE, yet the roles of Notch in uterine and placental vascular formation have not been fully investigated. In order to improve our understanding of physiologic uterine and placental vascular formation and the pathogenesis of PE, this study investigates Notch signaling in mouse PE models and human PE samples. We found that Notch signaling is active in the murine decidual vasculature that functions to support embryonic growth and development prior to placenta formation. In the placenta, we found that Notch signaling is active in both endothelial cells and trophoblasts, with distinct Notch protein and ligand expression. We hypothesize that Notch signaling regulates decidual angiogenesis and placental vascular formation and that disruption of Notch causes adverse pregnancy outcomes, including early miscarriages and PE. Genetic interventions in mice will be performed to define Notch function in the differentiation of placental endothelial cells and trophoblasts. We will evaluate P mouse models and human PE placental tissues for changes in Notch signaling. We present a novel approach to understanding the pathogenesis of PE and our study lays the foundation for developing tools to aide in early detection and/or management of PE and reduction of cardiovascular risk.

Public Health Relevance

Preeclampsia, a disease caused by vascular dysfunction in the placenta, is responsible for 15% of preterm births and is the second largest cause of maternal mortality worldwide. Notch signaling is a fundamental regulator for proper angiogenesis and vascular remodeling and our data implicate Notch function in decidual angiogenesis and the pathogenesis of preeclampsia. The studies will aid us in understanding Notch function in decidual angiogenesis and placenta formation and in developing tools for early detection and/or treatment of PE and reduction of cardiovascular risk.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL127013-01A1
Application #
9106632
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Maric-Bilkan, Christine
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032