Trophoblast dysfunction in pregnancy leads to defective placentation, resulting in small, apoptotic, and scarred placentas causing fetal growth restriction (FGR) and contributing to ~24% of stillbirths. Currently, there are no effective treatments, and the primary management strategy is preterm birth, which is the leading cause of neonatal morbidity and mortality, costing Australia $1.4 billion annually. The Hippo-YAP pathway, crucial for organ size regulation, cell proliferation, and survival, plays a vital role in early development and placental function. YAP dysregulation impairs trophoblast function and angiogenic gene expression. This study hypothesizes that targeting YAP can provide a therapeutic approach to improve pregnancy outcomes.
We assessed Yap gene expression in early (<34wks) and late (>34wks) matched preterm control, FGR, and preeclampsia+FGR cohorts. YAP expression is significantly downregulated in early (p<0.05) but not late preterm FGR cohort (compared to gestationally matched controls). At the protein level, there is significantly higher inactive (pYAP) protein in early preterm FGR placentas (p<0.01). While gene expression was indifferent in the preeclampsia+FGR cohorts, these placentas also show significant YAP inactivation (p<0.05). Overall YAP staining tends to be higher in FGR tissues, suggesting increased cytoplasmic retention and inhibition. We identified a therapeutic that significantly reduces YAP inhibition in primary trophoblasts (p<0.05), whole term (p<0.01) and FGR placental explants. In tissues, YAP reactivation reduces cleaved-caspase 3 apoptosis marker expression and enhances endothelial cell marker (CD31) expression.
We identified dysregulation in a key cellular growth pathway in FGR-affected placentas, evident in both FGR and preeclampsia+FGR cohorts. Our therapeutic successfully reversed this dysregulation at cellular and tissue levels, particularly affecting cytotrophoblast and endothelial cells. This led to increased cell proliferation and vascular staining in treated tissues. These findings have significant clinical implications, as reinstating YAP activity may restore cellular balance and vascularisation, improving placental function and potentially extending the gestation of FGR-affected pregnancies.