Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

Endothelial protein C receptor (EPCR) is deranged in preeclampsia  (#151)

Faith Andres 1 2 , Stephen Tong 1 2 , Natalie J Hannan 1 2 , Sue P Walker 2 , Teresa M MacDonald 1 2 , Ping Cannon 1 2 , Manju Kandel 1 2 , Josh Masci 1 2 , Tuong-Vi Nguyen 1 2 , Tu'uhevaha J Kaitu'u-Lino 1 2
  1. The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Road, Heidelberg 3084, Victoria, Australia
  2. Mercy Perinatal, Mercy Hospital for Women, Melbourne, Victoria, Australia

Preeclampsia impacts 2-8% of pregnancies and is characterised by placental and endothelial dysfunction(1). Endothelial Protein C receptor (EPCR) is localised to endothelial cells and abundantly expressed in placental trophoblasts(2). This study aimed to characterise EPCR in preeclampsia.

EPCR was measured in placentas from patients with preterm preeclampsia and both its mRNA and protein were significantly (p<0.0001) increased. Plasma EPCR and its ligand, Protein C (PROC) were then assessed (n=46 preeclampsia vs n=16 controls). Plasma EPCR was increased (p=0.0099), while PROC was decreased (p=0.0083) in preeclamptic patients. In contrast, circulating EPCR at 36 weeks’ gestation was not different in asymptomatic patients destined to develop preeclampsia at term (n=23 who later developed preeclampsia vs n=181 controls).  

Given preeclampsia is associated with placental hypoxia and inflammation, primary trophoblasts were exposed to hypoxia or the pro-inflammatory cytokine TNF-α. EPCR mRNA expression was increased following exposure to hypoxia (p=0.0079), whilst TNF-α dose dependently decreased (p=0.0005) EPCR. Metformin is a potential therapeutic for preeclampsia(3), thus we next assessed its effect on EPCR in isolated primary trophoblasts. Interestingly, metformin reduced EPCR expression. Finally, to assess whether circulating EPCR might also be sourced from dysfunctional maternal endothelium, primary endothelial cells (isolated from human umbilical vein endothelial cells) were treated with TNF-α, and endothelial dysfunction markers and EPCR assessed. Exposure to TNF-α induced dysfunction (elevated VCAM-1, ET-1), but significantly decreased EPCR expression (p=0.0079).

In conclusion, EPCR is increased in preterm preeclampsia. Placental hypoxia possibly contributes to this elevation and levels can be reduced by preeclampsia therapeutic metformin. Although EPCR is elevated in established disease, plasma EPCR is not altered preceding term diagnosis, therefore it is not a useful predictive biomarker. Further study will aid in elucidating the potential contribution of elevated placental EPCR to the pathogenesis of preeclampsia and determine its potential as a novel therapeutic target. 

 

 

 

 

 

 

 

 

  1. Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 222. Obstetrics & Gynecology. 2020;135(6):e237-e60.
  2. Li W, Zheng X, Gu J-M, Ferrell GL, Brady M, Esmon NL, et al. Extraembryonic expression of EPCR is essential for embryonic viability. Blood. 2005;106(8):2716-22.
  3. Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ, et al. Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. Am J Obstet Gynecol. 2016;214(3):356.e1-.e15.