The role of NOTCH pathway members in the development of pre-eclampsia

Pre-eclampsia is the leading cause of pregnancy complications worldwide and affects 3 to 8% of pregnancies. New Zealand studies have shown that the prevalence of pre-eclampsia is significantly higher in Maori women compared to their European counterparts.

The rapidly progressive condition is characterized by high blood pressure and the presence of protein in the urine. The disease is responsible for 18% of maternal deaths and up to 40% of fetal mortality. Pre-eclampia is strongly associated with fetal growth restriction, iatrogenic prematurity, placental abruption, and stillbirth of the child. The only known cure for the disease is the delivery of the placenta and the baby.

Although clinical signs are only apparent in later pregnancy, existing evidence strongly implicates molecular events leading to its onset which occur early in pregnancy. Inadequate placentation and poor placental perfusion are features of pre-eclampsia. In normal placental development, invasive trophoblast cells of fetal origin invade the maternal spiral arteries, transforming them into low resistance vessels capable of providing placental perfusion adequate to sustain the growing fetus. The primary impairment in pre-eclampsia is the failure of this transformation, resulting in increased vascular resistance and reduced placental perfusion. The molecular mechanisms responsible for the lack of trophoblast invasion are poorly understood.

The Notch signaling pathway directs differentiation and function during cell-cell contact in many tissues and is crucial for vascular patterning. Notch signaling has been implicated in trophoblast differentiation and invasion based on the presence of Notch receptors and ligands in different placental trophoblasts. Notch1, Notch2, Notch3, Notch4 and their ligands Jag1, Jag2, DLL1 and DLL4 are all found in the placenta. A recent report shows that cytotrophoblasts dramatically alter their expression of Notch receptors and ligands as they differentiate/invade. Active Notch signalling promotes invasion and the acquisition of an arterial endothelial cell-like phenotype in vitro. Decreased expression of Notch proteins are seen in the placentas of embryos affected by fetal growth restriction with an associated reduction in placental weight, implying a role for Notch signaling in human trophoblast proliferation. Expression of the Notch ligand JAG1 is absent in perivascular and endovascular trophoblasts in pre-eclampsia. The conditional deletion of Notch2 in mice in invasive trophoblasts leads to a significant reduction in placental perfusion and arterial invasion by trophoblasts. We have recently shown that there is a general down-regulation of NOTCH pathway members in placentas from pregnancies complicated with preeclampsia. Our results also show that NOTCH2 plays a crucial role in trophoblast invasion and migration in vitro.

This project aims to understand the mechanisms of NOTCH signalling in trophoblast invasion and differentiation.


Skills Taught:

Real-time PCR

Immunohistochemistry

SiRNA

Tissue and cell culture