Oral Presentation ESA-SRB-APEG-NZSE 2022

The lipoprotein receptor chaperone LRPAP1 is reduced in early pregnancy placenta and maternal serum from pregnancies that subsequently develop late-onset preeclampsia. (#47)

Ellen Menkhorst 1 2 , Wei Zhou 2 3 , Leiani Santos 1 2 , Kaori Koga 4 , Swati Varshney 3 5 , Nicholas Williamson 3 5 , Daniel Rolnik 6 , Fabricio Da Silva Costa 7 , Jon Hyett 8 , Argyro Syngelaki 9 , Kypros Nicolaides 9 , Evdokia Dimitriadis 1 2
  1. The University of Melbourne, Parkville, VIC, Australia
  2. Gynecology Research Centre, Royal Women's Hospital, Parkville, VIC, Australia
  3. University of Melbourne, Melbourne, VIC, Australia
  4. University of Tokyo, Tokyo, Japan
  5. Bio21 Institute, Parkville
  6. Department of Obstetrics and Gynecology, Monash Health, Melbourne
  7. Griffith University, Brisbane
  8. The University of Sydney, Sydney
  9. Fetal Medicine Foundation, London

Preeclampsia is a leading cause of maternal and fetal morbidity and mortality. Late-onset preeclampsia (>34 weeks gestation), accounts for >80% of preeclampsia but due to our poor understanding of the underlying etiology there is no predictive test and no preventative treatments. Whether there is an early pregnancy placental defect in late-onset preeclampsia has never been tested experimentally.

Mass spectrometry on early pregnancy placental biopsies (chorionic villous samples [CVS] collected 11-13 weeks gestation) compared placental protein production between uncomplicated and late-onset preeclamptic pregnancies (n=6-8/group). Placental LDL-receptor-related protein-associated protein (LRPAP1) expression across gestation was demonstrated by qPCR and immunohistochemistry/fluorescence. Circulating LRPAP1 in serum at 11-13 weeks gestation from uncomplicated and late-onset preeclamptic pregnancies (n=9-12/group) was quantified by ELISA. The effect of loss of LRPAP1 was determined by siRNA knockdown in the HTR8 trophoblast cell line (n=5).

Proteomics identified 48 significantly dysregulated proteins in CVS from late-onset preeclamptic pregnancies, which were enriched for molecular functions associated with protein binding and catalytic activity. LRPAP1 was significantly down-regulated in late-onset preeclamptic CVS (0.66-fold) and maternal serum (0.23-fold). Immunostaining revealed LRPAP1 expression by syncytiotrophoblast and cytotrophoblast in placental villous and extravillous trophoblast in decidua. Villous production (mRNA) of LRPAP1 fell significantly at 13-16 weeks gestation compared to 8-10 and 18-21. In vitro, LRPAP1 regulated production of the cholesterol metabolism modulators NCEH1 and CAV1, and loss of LRPAP1 impaired trophoblast adhesion, proliferation and invasion.

This is the first study to demonstrate that the early pregnancy placenta is altered in pregnancies that go on to develop late-onset preeclampsia. LRPAP1 may be central to the placental dysfunction of late-onset preeclampsia: LRPAP1 regulates clearance of multiple lipoproteins; lipoproteins including cholesterol show excess placental accumulation in preeclampsia. This study provides much-needed insight into the placental dysfunction of late-onset preeclampsia, which will facilitate the development of predictive tests and preventative treatments.