Abstract
ContextPreeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies.ObjectiveTo investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44.Design and InterventionFKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling.Settings and ParticipantsHuman samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, 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 MeasuresPreeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed.ResultsThe CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>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 signaling, enhancing cell angiogenesis.ConclusionsThe FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.
Highlights
Plasma FK506-binding protein like (FKBPL) concentration was increased in women with preeclampsia compared to controls (Fig. 1A; 0.81 ng/ mL ± 0.018 standard error of the mean (SEM) vs 0.76 ng/mL ± 0.011 SEM, P < 0.05) whereas plasma CD44 concentration was decreased in the same samples (Fig. 1B; 85.1 ng/mL ± 4.2 SEM vs 104.7 ng/mL ± 4.9 SEM, P < 0.01)
The CD44/FKBPL ratio was significantly reduced in preeclampsia cases compared to controls (Fig. 1C; 105.3 ng/mL ± 5.5 SEM vs 136.3 ng/mL ± 5.2, P < 0.001)
Our results show that the CD44/FKBPL ratio is associated with the risk of preeclampsia independently of established risk factors including age, body mass index (BMI), mean arterial blood pressure (MAP), and weight gain [33,43,44], from 20 weeks of gestation
Summary
In combination with high mean arterial blood pressure (>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 signaling, enhancing cell angiogenesis. Other predictive algorithms have been used successfully early in pregnancy between 11 and 13 weeks of gestation based on maternal characteristics, uterine artery pulsatility index and angiogenic factors such as PlGF and PAPP-A [8]. These are mainly effective at predicting early-onset or preterm preeclampsia. In preclinical models of preeclampsia, MSCs demonstrated therapeutic efficacy [12,13], likely through paracrine signaling; the underlying mechanisms are not yet well understood [14,15]
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