48. ELABELA and placental development in pregnancy and preeclampsia

Abstract

The peptide hormone ELABELA (ELA) was discovered in 2013 and found to be essential for zebrafish cardiovascular development through activation of the Apelin receptor (APLNR). In humans, ELA has been found to be expressed in adult kidney and prostate, and in embryonic pluripotent stem cells where it serves as a growth factor, but signals via a yet unidentified second receptor. To further investigate the contribution of ELA to mammalian development ELA knockout mice were generated. The knockout embryos showed clear cardiovascular defects, but also the placentas were affected, which may lead to preeclampsia-like symptoms in ELA knockout mothers. Indeed, the mice showed significantly increased blood pressure and proteinuria. Remarkably, infusion of synthetic ELA was able to entirely rescue blood pressure, proteinuria, and increase fetal birth weight. The above findings let to studying ELA in human placentation and preeclampsia (PE). ELA was localized in villous cytotrophoblasts and, as expected for a hormone, in the syncytiotrophoblast layer of first trimester placental tissues. High expression was also observed in invading extravillous trophoblasts. In trophoblast cell lines ELA addition significantly increased the invasive capacity of these cells as measured in transwell invasion assays. In first trimester placental explant cultures ELA changed the morphology of the extravillous outgrowth and decreased trophoblast proliferation. Interestingly, preliminary results suggest that these downstream effects of ELA are not initiated by ELA binding to the Apelin receptor, therefore the second unknown receptor must be considered instead. Finally, circulating ELA in plasma of healthy and PE pregnancies measured at multiple time points in gestation did not appear to be associated with PE development. However, ELA’s peptide properties were found to interfere with the initial measurements done. These technical issues therefore first need to be resolved before definite conclusions can be drawn on the applicability of ELA as potential PE biomarker.