Complement and coagulation cascades activation is the main pathophysiological pathway in early-onset severe preeclampsia revealed by maternal proteomics

Abstract

Preeclampsia is a pregnancy-specific multisystem disorder and a leading cause of maternal and perinatal morbidity and mortality. The exact pathogenesis of this multifactorial disease remains poorly defined. We applied proteomics analysis on maternal blood samples collected from 14 singleton pregnancies with early-onset severe preeclampsia and 6 uncomplicated pregnancies to investigate the pathophysiological pathways involved in this specific subgroup of preeclampsia. Maternal blood was drawn at diagnosis for cases and at matched gestational age for controls. LC-MS/MS proteomics analysis was conducted, and data were analyzed by multivariate and univariate statistical approaches with the identification of differential pathways by exploring the global human protein-protein interaction network. The unsupervised multivariate analysis (the principal component analysis) showed a clear difference between preeclamptic and uncomplicated pregnancies. The supervised multivariate analysis using orthogonal partial least square discriminant analysis resulted in a model with goodness of fit ((RX)-X-2 = 0.99, p < 0.001) and a strong predictive ability (Q(2)Y = 0.8, p < 0.001). By univariate analysis, we found 17 proteins statistically different after 5% FDR correction (q-value < 0.05). Pathway enrichment analysis revealed 5 significantly enriched pathways whereby the activation of the complement and coagulation cascades was on top (p = 3.17e-07). To validate these results, we assessed the deposits of C5b-9 complement complex and on endothelial cells that were exposed to activated plasma from an independent set of 4 cases of early-onset severe preeclampsia and 4 uncomplicated pregnancies. C5b-9 and Von Willbrand factor deposits were significantly higher in early-onset severe preeclampsia. Future studies are warranted to investigate potential therapeutic targets for early-onset severe preeclampsia within the complement and coagulation pathway

This project has been partially funded with support of the Erasmus+ Programme of the European Union (Framework Agreement number: 2013-0040). This publication reflects the views only of the author, and the Commission cannot be held responsible for any use, which may be made of the information contained therein. Additionally, the research leading to these results has received funding form "la Caixa" Foundation under grant agreements LCF/PR/GN14/10270005 and LCF/PR/GN18/10310003, the Instituto de Salud Carlos III (PI14/00226, PI15/00130, PIE15/00027, PI17/00675, PI18/00073) integrados en el Plan Nacional de I+D+I y cofinanciados por el ISCIII-Subdireccion General de Evaluacion y el Fondo Europeo de Desarrollo Regional (FEDER) "Una manera de hacer Europa", Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK) and AGAUR 2017 SGR grant no 1531, Fundacio La Marato de TV3 (Project Code: 202026). OT was supported by Miguel Servet grant from the Instituto de Salud Carlos III (CP17/00114). This research used the Hospital Clinic-IDIBAPS Biobank resource. We thank the patients for participating in this study and the nurses from the Departments of Maternal-Fetal Medicine at BCNatal (Barcelona, Spain) for their help in collecting human samples. We also thank Jordi Mayneris from the Proteomics facility of the Centre for Omic Sciences Joint Unit of the Universitat Rovira i Virgili-Eurecat for their contribution to the proteomics and bioinformatics analysis. The KEGG map of the complement and coagulation cascades was used under permission from Kanehisa Laboratories