Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria

Anna Middleton,Sebastián E Illanes ,Gaby S Pell ,Manuel Schepeler,Cíara Murphy ,Ping Cannon,Elizabeth Murray,Emerson Keenan,Tu’uhevaha J Kaitu’u-Lino ,Alexandra Roddy Mitchell,Teresa M Macdonald,J Nien ,Joshua Masci,Tess Cruickshank,Georgia Wong ,Jon Hyett,Susan Walker ,Carole Anne Whigham ,Natalie J Hannan,Manju Kandel,Jenny Myers,Damanpreet Garcha,Fiona Brownfoot,Jessica Jellins,Tuong Vi Nguyen ,Stephen Tong,Natasha Pritchard

doi:10.1038/s41598-021-96077-1

Abstract

Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks’ gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24–34 weeks’ gestation); two prospective cohorts collected on the day of delivery (36 + 3–41 + 3 weeks’ gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.

Highlights

Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy
Examining six independent cohorts from three countries we have robustly validated the hypothesis that syndecan-1 is significantly reduced in the maternal circulation in pregnancies complicated by small for gestational age (SGA) or fetal growth restricted (FGR)
We have provided evidence that placental secretion of syndecan-1 may be regulated by Matrix metalloproteinase (MMP) via a post translational mechanism

Summary

Introduction

Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses. Small-for-gestational-age (SGA) fetuses form a major proportion of pregnancies with poor perinatal outcome given many have true placental insufficiency and fetal growth restriction (FGR)[1]. Syndecan-1 was identified as a second potential candidate as circulating levels were significantly reduced at 36 weeks’ gestation in 97 women destined to deliver an SGA infant at term relative to 901 controls[8]. Syndecan-1 was not followed up further and the findings were not validated

Objectives

Methods

Results

Conclusion