Lightning Talk + Poster ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Targeting the vasoconstrictor, endothelin 1, to improve understanding of preeclampsia and investigate potential treatments (#417)

Natalie K Binder 1 , Natasha de Alwis 1 , Bianca R Fato 1 , Anjali Garg 1 , Lydia Baird 1 , Sally Beard 1 , Keegan Chien 1 , Teresa M MacDonald 2 , Tu'uhevaha J Kaitu'u-Lino 2 3 , Sue P Walker 2 , Stephen Tong 2 3 , Natalie J Hannan 1
  1. Therapeutic Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics, Gynaecology & Newborn Health, University of Melbourne, Heidelberg, Victoria, Australia
  2. Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
  3. Translational Obstetrics Group, Department of Obstetrics, Gynaecology & Newborn Health, University of Melbourne, Heidelberg, Victoria, Australia

Preeclampsia is a devastating complication of pregnancy featuring profound injury to systemic vasculature, major organs, and the feto-placental unit. Preeclampsia also substantially increases cardiovascular disease risk. Implicated in the pathogenesis of both diseases is the vasoconstrictor, endothelin (ET)1. We aimed to evaluate concentrations of ET1 both prior to and after the onset of preeclampsia, as well as selective in vitro inhibition of the ET1 receptors, ETA and ETB, to assess disease modulating capabilities.

 

Blood was collected from 1) an established early onset preeclampsia cohort <34-weeks’ gestation and 2) a prospective cohort at 28- and 36-weeks’ gestation prior to diagnosis of term preeclampsia (and gestation matched controls). Serum ET1 concentration was determined by ELISA. Isolated primary human umbilical vein endothelial cells (HUVECs), placental tissue explants, and omental arteries collected at caesarean section were treated with BQ123 and BQ788, selective inhibitors of ETA and ETB, respectively. Secretion of anti-angiogenic soluble fms-like tyrosine kinase (sFLT)1 was assessed by ELISA. Expression of antioxidant heme oxygenase 1, pro-inflammatory cytokine interleukin-1b, and marker of endothelial dysfunction vascular cell adhesion molecule (VCAM) were assessed by qPCR. Vascular reactivity was assessed via wire myography.

 

Circulating ET1 was significantly increased in established preterm preeclampsia (2.46 ± 0.18 pg/mL) compared to controls (0.87 ± 0.06 pg/mL) (p<0.0001), as well as significantly elevated at both 28-weeks’ (p<0.001) and 36-weeks’ (p<0.05) gestation, prior to development of term disease. Inhibition of ETA and ETB did not affect gene expression or sFLT1 secretion in HUVECs and placental explants. Inhibition of ETA, but not ETB, significantly decreased vasoconstriction in response to ET1.

 

Circulating ET1 is significantly elevated both prior to and following the onset of preeclampsia. Blocking ETA receptor reduced vasoconstriction, but blocking ETA and ETB did not reduce VCAM or sFlt-1 secretion, that drive endothelial dysfunction. Further studies are needed to determine therapeutic utility.