PAPP-A2 in the Pathogenesis of Pre-eclampsia — ASN Events

PAPP-A2 in the Pathogenesis of Pre-eclampsia (#77)

Kathleen R Macintire 1 , Laura Tuohey 1 , Louie Ye 1 , Clare L Whitehead 1 , Stephen Tong 1 , Tu'uhevaha J Kaitu'u-Lino 1
  1. University of Melbourne, Heidelberg, VIC, Australia

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.