The deregulated interplay of complement system and antioxidant activity as a driver of adverse pregnancy outcomes

The placenta remains the key to maternal diseases such as Pre-eclampsia (PE) and Intrauterine growth restriction (IUGR), however the pathophysiology of these disorders remains elusive. The aim of this study is to characterize the key proteomic variations between PE and IUGR, to better understand the pathoetiology of these diseases.Term placentas each were collected from PE, IUGR pregnancies, and age and BMI matched healthy controls. Quadrupole-orbitrap mass spectrometer was used in data dependent analysis mode to identify differentially expressed proteins (DEP) between conditions. Functional analysis was conducted using Perseus, ClusterCompare, NaviCenta disease map and TriplexRNA database. A core regulatory network based on log2FC and rewiring scores including regulating miRNAs and transcription factors was constructed using Cytoscape DyNet.In total 314, 391, and 378 proteins were identified in normal, PE, and IUGR placenta, respectively. Venn diagram analysis revealed that 35 proteins were unique to PE placenta, 17 proteins were unique to IUGR and 3 proteins were unique to healthy control placentas. Focusing results further applying a threshold log2FC >0.5, we identified nine DEPs between the conditions. Functional analysis combining ClusterCompare and NaviCenta to analyze a placenta-centric context, showed that regulatory elements are predominantly involved in complement cascade and antioxidant activities. Our results further highlight two RNA triplexes involved in the core regulatory module in PE and IUGR placentas, both targeting PSAP mRNA.Our results identify new potential regulatory proteins in PE and IUGR pathology. The identified miRNA triplexes further open up a novel avenue of investigation for placenta research.