Kim Phan, McGill University

Supervisor: Stella Daskalopoulou, McGill University

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy that carries serious implications for women’s health. Not only can this complication lead to severe maternal and neonatal outcomes, but women who have a history of PE are at 3-fold increased risk for hypertension and 2-fold increased risk for cardiovascular (CV) events as early as 10 years post-partum. It is believed that PE initiates from impaired trophoblast invasion of the spiral arteries in the first trimester. However, clinical manifestations of the consequent placental dysfunction do not appear until the second half of pregnancy. Our overall objective is to capitalize on this window and develop a strategy for the early prediction of PE. Currently, there is no accurate predictive tool in clinical practice.

This project will identify the role of circulating syncytiotrophoblast microparticle (STBM)-derived microRNA in endothelial dysfunction and evaluate its predictive value as an early biomarker for PE. We will compare the profile of syncytiotrophoblast microparticles and their microRNA content between women who are diagnosed with PE and women with uncomplicated pregnancies. Using primary cultures of human umbilical vein endothelial cells, we will assess whether microRNAs are transferred to endothelial cells through internalization of STBM and whether their dysregulated microRNA content alters the cellular mRNA and protein expression. Finally, we will evaluate the changes in the endothelial cell function associated with dysregulated microRNA including cell proliferation, migration, and apoptosis. Building on existing efforts of the REVEAL study, we will validate identified microRNA for their predictive value in PE.

Our proposal addresses the priority of the Canadian Vascular Network to “identify novel methods of early detection of vascular conditions”. We will broaden our understanding of the role of microRNA in endothelial dysfunction and provide evidence for the utility of microRNA as an early predictive biomarker for PE. Identification of underlying pathways in PE progression would have significant impact on  reducing maternal and fetal morbidity by presenting an opportunity for effective targeted clinical interventions. Furthermore, a better understanding of the processes underlying the vascular impairment in PE would initiate efforts to develop future targeted prophylactic therapies against STBM-induced endothelial dysfunction. We suspect the temporal stress of pregnancy may unmask the subclinical endothelial dysfunction, which predisposes these women to CV events later in life. Use of microRNA biomarkers may also be an important clinical tool for the post-partum monitoring of vascular function. For many women, their first encounter with the public health system is at the time of pregnancy. Thus, early detection of PE may also be the first opportunity for early screening of women at risk for future CV disease with the ultimate goal of reducing the burden of vascular disease and promoting healthy aging in women.