Metabolomics Identifies Placental Dysfunction and Confirms Flt-1 (FMS-Like Tyrosine Kinase Receptor 1) Biomarker Specificity

Abstract

Clinical end-stage parameters define the pregnancy disorders preeclampsia and fetal growth restriction while classification of the underlying placental dysfunction is missing and urgently needed. Flt-1 (FMS-like tyrosine kinase receptor 1) is the most promising placenta-derived predictive biomarker for preeclampsia. We aimed to classify placental dysfunction in preeclampsia and fetal growth restriction at delivery by metabolic profiling and authenticate the biomarker Flt-1 for placental dysfunction. We studied 143 pregnancies with or without preeclampsia and/or fetal growth restriction delivered by cesarean section. Metabolic placenta profiles were created by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy and the resulting placental phenotypes obtained by hierarchical clustering. Placental Flt-1 expression (membrane-bound and soluble isoforms combined) and maternal serum Flt-1 expression (soluble isoforms) were analyzed by immunohistochemistry and ELISA, respectively. We identified 3 distinct placenta groups by 21 metabolites and diagnostic outcome parameters; normal placentas, moderate placental dysfunction, and severe placental dysfunction. Increased placental Flt-1 was associated with severe placental dysfunction, and increased serum Flt-1 was associated with moderate and severe placental dysfunction. The preeclamptic pregnancies with and without placental dysfunction could be distinguished by 5 metabolites and placental Flt-1. Placental Flt-1 alone could separate normal pregnancies with and without placental dysfunction. In conclusion, metabolomics could classify placental dysfunction and provide information not identified by traditional diagnostics and metabolites with biomarker potential were identified. Flt-1 was confirmed as precision biomarker for placental dysfunction, substantiating its usefulness for identification of high-risk pregnancies for preeclampsia and fetal growth restriction with placental involvement.

Long Non-Coding RNA Nuclear-Enriched Abundant Transcript 1 (NEAT1) Represses Proliferation of Trophoblast Cells in Rats with Preeclampsia via the MicroRNA-373/FLT1 Axis

“…The bioinformatics website suggested that FLT1 is a potential target of miR-373 ( Figure 4A ), in agreement with results showing that FLT1 expression enhances the likelihood of PE [ 14 ]. The expression of FLT1 was much higher in PE than in control rats ( Figure 4B ).…”

TLR3 expression by maternal and fetal cells at the maternal-fetal interface in normal and preeclamptic pregnancies

“…The heterogeneous disorder preeclampsia consists of distinct subtypes that go beyond the current diagnostic measures. 22,47 Different ongoing pathologic processes at the maternal-fetal interface might…”

“…The heterogeneous disorder preeclampsia consists of distinct subtypes that go beyond the current diagnostic measures 22,47 . Different ongoing pathologic processes at the maternal‐fetal interface might give the same clinical symptoms in the preeclamptic mother and a better classification of the disorder taking placenta dysfunction into account would lead to improved understanding, screening, and treatment of the disease.…”

“…Both tissue types were fixed in 10% formalin and paraffin embedded. Metabolomics profiling of the placental tissue was used to distinguish pregnancies with normal placental function from pregnancies with moderate and severe placental dysfunction 22 …”

How could metabolomics change pediatric health?

“…According to another study, metabolomics placental profiles could also be useful in identifying PE with placental dysfunction and even associated IUGR [46].…”