Angiogenic and vasoactive proteins in the maternal-fetal interface in healthy pregnancies and preeclampsia

Abstract

Preeclampsia is characterized by maternal endothelial activation and placental dysfunction. Imbalance in maternal angiogenic and vasoactive factors has been linked to the pathophysiology. The contribution of the placenta as a source to these factors remains unclear. Furthermore, little is known about fetal angiogenic and vasoactive proteins and the relation between maternal and fetal levels. We describe Placental growth factor (PGF), soluble Fms-like tyrosine kinase 1 (sFLT1), soluble Endoglin (sENG), as well as Endothelin 1, 2 and 3 (EDN1, EDN2 and EDN3) in five vessels in healthy pregnancies, early onset (EOPE) and late onset (LOPE) preeclampsia. Specifically, we aimed to 1) compare protein abundance in vessels at the maternal-fetal interface between EOPE, LOPE and healthy pregnancies, 2) describe placental uptake and release of proteins, and 3) describe protein abundance in the maternal vs fetal circulations. Samples were collected from the maternal radial artery, uterine vein and antecubital vein as well as the fetal umbilical vein and artery in 75 healthy and 37 preeclamptic mother-fetus pairs (including 19 EOPE and 18 LOPE), during scheduled cesarean delivery. This method allows estimation of placental release and uptake of proteins by calculation of venoarterial differences on each side of the placenta. The microarray based SomaScan assay quantified the proteins. Abundance of sFLT1 and EDN1 was higher in the maternal vessels in preeclampsia as compared to healthy pregnancies, with highest abundance in EOPE. PGF was lower in the maternal vessels in EOPE as compared to both healthy and LOPE. Maternal EDN2 was higher in preeclampsia, with LOPE having the highest abundance. Our model confirmed placental release of PGF and sFLT1 to the maternal circulation in all groups. The placenta released sFLT1 into the fetal circulation in healthy and LOPE pregnancies. Fetal EDN1 and sFLT1 were higher in early onset preeclampsia, whereas sENG and EDN3 were lower in both preeclampsia groups, compared to healthy. Across groups, abundances of PGF, sFLT1 and EDN3 were higher in the maternal artery as compared to the fetal umbilical vein, whereas EDN2 was lower. Increasing abundance of maternal sFLT1 and EDN1 across the groups healthy, LOPE and EOPE combined with a positive correlation may suggest that these proteins are associated with the pathophysiology and severity of the disease. Elevated EDN1 in the fetal circulation in EOPE represents a novel finding. Long term effects of altered protein abundance in preeclampsia on fetal development and health remain unknown. Further investigation of these proteins' involvement in the pathophysiology and as treatment targets is warranted.