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Developmental Biology - Pre-eclampsia
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A novel discovery of two new biomarkers might lead to early diagnosis of deadly preeclampsia in pregnancy. This discovery has the potential to predict underlying causes of preeclampsia — leading to its early diagnosis.
Preeclampsia is devastating. It occurs very suddenly in the second half of pregnancy, causing severe health problems for both mother and baby. It also increases a mother's risk of developing life-long chronic diseases such as diabetes and heart disease.
The discovery of two novel biomarkers, called FKBPL and CD44, has the potential to change the way the condition is managed according to research published in the Journal of Clinical Endocrinology and Metabolism.
Preeclampsia can cause high blood pressure and organ failure in mothers and lead to preterm births and even stillbirth. Senior author, Dr Lana McClements from the University of Technology Sydney, Australia, believes the biomarkers can be used to diagnose and assess risk for getting preeclampsia in both early and late pregnancy, "in women who otherwise appear healthy."
"There are two main types of preeclampsia: early-onset preeclampsia diagnosed before 34 weeks of a pregnancy, and late-onset preeclampsia diagnosed from 34 weeks onwards.
The vast majority of current screening and monitoring strategies are focused on early-onset preeclampsia, which comprises only 10-15% of all preeclampsia cases, whereas late preeclampsia has largely been neglected."
Lana McClements, MPharm, PhD
The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
School of Life Sciences, Faculty of Science, University of Technology Sydney, Australia and Corresponding author.
Researchers say the two biomarkers are particularly useful for diagnosing cases of late-onset preeclampsia, between the second and third trimester, a period that currently has no reliable biomarkers.
"The biomarkers allow the prediction of irregular placenta or maternal vascular function, which are key underlying causes of preeclampsia. This could lead to the early diagnosis and prevention of severe preeclampsia and associated complications including death, therefore also giving insight into disease mechanisms and possible treatment targets," explains McClements.
This research has the potential to enhance therapeutic development for treatment of preeclampsia. It increases one of the biomarkers, FKBPL, which can then be inhibited by mesenchymal stem cells and potentially stop development of the disorder.
"This is why we are so excited by the discovery. In addition to their use in diagnosis, FKBPL and CD44 also show potential for drug and cell therapy targets in treatment for preeclampsia, offering hope for a future cure to this terrible disorder," adds McClements.
Abstract Context
Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies.
Objective
To investigate the diagnostic and therapeutic potential of the angiogenesis markers, FKBPL-CD44, in preeclampsia pathogenesis.
Design and Intervention
FKBPL and CD44 plasma or placental concentration was determined in women pre- or post-diagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signalling.
Settings and Participants
Human samples pre-diagnosis (15 and 20 weeks’ gestation; n>=57), or post-diagnosis (n=18 for plasma; n=4 for placenta) of preeclampsia were used to determine FKBPL and CD44 concentration, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid.
Main outcome Measures
Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signalling in trophoblast and endothelial cells were assessed.
Results
The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks’ gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.5-fold increased risk of preeclampsia (OR=2.5, 95% CI 1.12-5.41, p=0.02). In combination with high mean arterial blood pressure (MABP > 82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, p=0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signalling enhancing cell angiogenesis.
Conclusions
The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.
Authors
Naomi Todd, PhD, Ross McNally, BSc, Abdelrahim Alqudah, PhD, BPharm, Djurdja Jerotic, MD, Sonja Suvakov, MD, PhD, Danilo Obradovic, MD, Denise Hoch, MSc, Jose R Hombrebueno, PhD, Guillermo Lopez Campos, PhD, Chris J Watson, PhD, Miroslava Gojnic-Dugalic, MD, PhD, Tatjana P Simic, MD, PhD, Anna Kransodembskaya, PhD, Gernot Desoye, PhD, Kelly-Ann Eastwood, MBBS PhD, Alyson J Hunter, MD, Valerie A Holmes, PhD, David R McCance, MD, Ian S Young, MD, David J Grieve, PhD, Louise C Kenny, MD, PhD, Vesna D Garovic, MD, PhD, Tracy Robson, PhD, Lana McClements, MPharm, PhD.
Acknowledgements
Other institutions involved in the research are Queen's University Belfast, UK; Medical University Graz, Austria; Royal College of Surgeons in Ireland, Ireland; University College Cork, Ireland; University of Liverpool, UK; University of Belgrade, Serbia; The Hashemite University, Jordan; Mayo Clinic, USA; Belfast Health and Social Care Trust, UK
The study was published as an accepted manuscript in November 2019 but appeared as a final publication on March 31 2020.
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