Human placental bed transcriptomic profiling reveals inflammatory activation of endothelial cells in preeclampsia

Abstract

RationaleFunctional characteristics of endothelial cells (ECs) within the human placental bed are unknown and may provide insight into the adaptive biology of ECs in disorders of vascular remodelling like preeclampsia. ObjectiveTo determine transcriptional profiles of human placental bed ECs and systemic biomarker profiles in women with normal pregnancy, and women with preeclampsia, a condition characterized by extensive EC dysfunction, poor development of spiral arteries underlying the placenta and long-term susceptibility to atherosclerosis and hypertension. Methods & resultsWe obtained biopsy samples from the uterine placental bed, of five women with preeclampsia with fetal growth restriction (FGR) due to impaired spiral artery development and four controls undergoing Caesarean section. CD31+CD146+ ECs were isolated and sorted by flow cytometry for RNA-sequencing using CEL-Seq2 protocol. Data were analyzed by unsupervised clustering, gene set enrichment (GSEA) and pathway analysis. 67 circulating biomarkers of EC function and inflammation were measured in 20 women with preeclampsia with FGR and 20 controls by multiplex immunoassay. Transcriptional profiling showed various differentially expressed genes (FDR<0.05) in placental bed ECs of preeclampsia patients, with enhanced activity of pathways associated with vasoconstriction, platelet activation and innate immunity. GSEA was suggestive of a VEGF- and PlGF deprived state of preeclampsia-derived ECs. Moreover, the transcriptomic profile was similar to that of human umbilical vein endothelial cells (HUVECs) treated with plasma from preeclampsia patients, pointing towards a central role for circulating factors in EC dysfunction. Unsupervised clustering of subjects by EC-related circulating factors identified distinct profiles for healthy pregnancy and preeclampsia, in particular for those women with low platelets and elevated liver enzymes, which was predominantly driven by sFLT-1, endoglin, PlGF, leptin, SAA-1 and sICAM-1. ConclusionsWe revealed inflammatory activation of EC and a key role for systemic factors in EC dysfunction in women with preeclampsia associated with impaired spiral artery development.