Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Preeclampsia (PE) is a multifactorial gestational disorder characterized by pathologically elevated maternal blood pressure and proteinuria. PE occurs in approximately 5-10% of all human pregnancies and is one of the leading causes of fetal morbidity and mortality in the developed world. Currently the precise cause of PE is unknown and there is no cure; the only effective treatment is induction of labour and delivery of the placenta. Although the specific causes of PE are unknown, the expression of the angiogenic signalling molecule placental growth factor (PGF) has been shown to be necessary for normal placentation changes during pregnancy. Furthermore, antagonism of PGF by soluble fms-like tyrosine kinase-1 (sFLT1) or S-endoglin has been shown to induce PE-like lesions. Recent evidence has shown that circulating plasma PGF levels decrease significantly immediately prior to the onset of PE in humans, while circulating sFLT1 levels increase significantly during the same timeframe. Interestingly, PGF is expressed by both fetal trophoblasts and maternal uterine natural killer (uNK) cells during pregnancy. However, it has never been established which source of PGF is responsible for directing normal placentation changes during pregnancy. Additionally, the pattern of PGF expression during mouse pregnancy has not been determined, and thus it is unknown if the changes in PGF expression which occur over course of pregnancy in humans are mirrored in mice. Furthermore, an effective animal model for studying the fetal and maternal contributions to PGF expression and normal placentation has never been established. In this study, we propose to determine the precise profile of plasma PGF levels throughout the course of mouse pregnancy in wild-type and alypmhoid mice lacking uNK cells. In addition, through embryo transfer experiments, we propose to determine the exact contributions of fetal and maternal-derived PGF in regulating placentation changes leading to PE.