Peptide hormone ELABELA enhances extravillous trophoblast differentiation, but placenta is not the major source of circulating ELABELA in pregnancy

Abstract

Preeclampsia is a frequent gestational hypertensive disorder with equivocal pathophysiology. Knockout of peptide hormone ELABELA (ELA) has been shown to cause preeclampsia-like symptoms in mice. However, the role of ELA in human placentation and whether ELA is involved in the development of preeclampsia in humans is not yet known. In this study, we show that exogenous administration of ELA peptide is able to increase invasiveness of extravillous trophoblasts in vitro, is able to change outgrowth morphology and reduce trophoblast proliferation ex vivo, and that these effects are, at least in part, independent of signaling through the Apelin Receptor (APLNR). Moreover, we show that circulating levels of ELA are highly variable between women, correlate with BMI, but are significantly reduced in first trimester plasma of women with a healthy BMI later developing preeclampsia. We conclude that the large variability and BMI dependence of ELA levels in circulation make this peptide an unlikely candidate to function as a first trimester preeclampsia screening biomarker, while in the future administering ELA or a derivative might be considered as a potential preeclampsia treatment option as ELA is able to drive extravillous trophoblast differentiation.

ZBED1 Regulates Genes Important for Multiple Biological Processes of the Placenta

“…The effect of ZBED1 knockdown on gene expression was most pronounced 24 h after forskolin treatment, suggesting that ZBED1 might be important in the early stages of trophoblast differentiation. In addition to significant induction of genes favoring differentiation and invasion (e.g., APELA [ 50 ], BGN [ 51 ], HSPB1 [ 52 ], INHA [ 53 ], KLF4 [ 54 ], SGK1 [ 55 ], and TBX3 [ 56 ]), ZBED1 knockdown also induced expression of syncytiotrophoblast markers (e.g., ERVFRD-1 [ 17 ], CYP19A1 [ 20 ], and DYSF [ 19 ]) and repressed cytotrophoblast makers (e.g., ID-1 [ 57 ], CAV1 [ 46 , 58 ], ELF-5 [ 59 ], and NR6A1 [ 60 ]) that also inhibit differentiation and are crucial for cytotrophoblast maintenance. Normally these genes are highly expressed in CTBs, but their expression diminishes during differentiation.…”

The Role of the Adipokines in the Most Common Gestational Complications

“…It was proposed that deficiency in the placental elabela (ELA) secretion (a protein, ligand of the APJ) may be liable for the abnormal early placentation and as a consequence could lead to the development of PE in the murine model [ 231 ]. It was established that ELA has a capacity to increase the trophoblast invasiveness in vitro [ 232 ]. The pathogenesis of preeclampsia is also believed to be connected with the vascular endothelial dysfunction [ 233 ].…”

Maternal plasma Elabela levels in intrauterine growth restriction

“…In a previous study it was shown that exogenous administration of Elabela peptide could increase the invasiveness of extravıllous trophoblasts in vitro, change the growth morphology, and reduce ex vivo trophoblast proliferation. However, it was emphasised that Elabela levels in circulation in women are extremely variable, they are correlated with BMI, and are significantly reduced in the plasma in the first trimester of women with a healthy BMI who develop pre-eclampsia 17 . With the consideration that BMI affects the maternal serum Elabela level, the IUGR and control groups of the current study were formed of subjects with similar BMI values to eliminate this effect.…”