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

Damanpreet Garcha, Susan P. Walker, Teresa M. MacDonald, Jon Hyett, Jessica Jellins, Jenny Myers, Sebastian E. Illanes, Jhy K. Nien, Manuel Schepeler, Emerson Keenan, Carole Anne Whigham, Ping Cannon, Elizabeth Murray, Tuong Vi Nguyen, Manju Kandel, Joshua Masci, Ciara Murphy, Tess Cruickshank, Natasha Pritchard, Natalie J. HannanFiona Brownfoot, Alexandra Roddy Mitchell, Anna Middleton, Gabrielle Pell, Georgia P. Wong, Stephen Tong, Tu’uhevaha J. Kaitu’u-Lino

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number16595
JournalScientific Reports
Volume11
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
Funding for this work was provided by the National Health and Medical Research Council (#1065854, #1183854, #116071), an Australian Government Research Training Program Scholarship, and RANZCOG Taylor Hammond Scholarship to TM; National Health and Medical Research Council Fellowships to TKL (#1159261), NJH (#1146128), ST (#1136418). The funders played no role in study design or analysis.

Funding Information:
from the RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan and cultured according to the publication from Okae and colleagues28. Syncytiotrophoblasts were differentiated from cyto-trophoblasts as previously described28.

Publisher Copyright:
© 2021, The Author(s).

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