PAPP-A2 in the Pathogenesis of Pre-eclampsia (#77)
Pre-eclampsia (PE) is a severe disease affecting 4-8% of pregnancies and accounting for 20% of maternal deaths worldwide. PE is believed to arise as a result of persistent placental hypoxia due to insufficient placentation. Pregnancy-associated plasma protein-A2 (PAPP-A2, Pappalysin-2) is a novel homolog of PAPP-A of the metzincin superfamily1. In silico analysis shows 700-fold placental PAPP-A2 expression compared to other human tissues, whilst our previous data indicates a 20-fold up-regulation in PE compared to term placental mRNA expression. The objective of this study was to characterise PAPP-A2 protein expression and determine its functional role in the PE placenta. Real time RT-PCR and Western Blot confirmed PAPP-A2 mRNA and protein expression in a cohort of severe early onset PE placentas (n=17) and gestationally matched pre-term controls (n=12). Immunohistochemistry revealed PAPP-A2 protein was localised to the syncytiotrophoblast in PE and preterm placenta, however no expression was detected in term placental tissue. Using the choriocarcinoma BeWo cell line, we demonstrated a significant (p<0.05) decrease in PAPP-A2 mRNA and protein expression with syncytialisation (confirmed by hCG ELISA). Given PAPP-A2 has a putative hypoxic recognition site in its promoter region, we next assessed PAPP-A2 mRNA and protein expression in BeWo cells and primary placental explants following exposure to hypoxia (1% oxygen). In both BeWo cells and placental explants, hypoxia induced a significant (p<0.001) increase in PAPP-A2 mRNA and protein expression.
Together this data suggests that PAPP-A2 may become dysregulated during the early pathogenesis of PE when there is persistant hypoxia resulting in over-expression that contributes to the ongoing placental dysfunction observed in PE.