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Circulating immune cells from early- and late-onset preeclampsia displays distinct profiles with differential impact on endothelial activation

ABSTRACT: Preeclampsia (PE) affects 5-8% of pregnancies and has detrimental effects on maternal-fetal health. PE is characterized by de novo hypertension after 20 weeks of gestation and end-organ damage. Systemic inflammatory imbalance has been associated with PE, but its contribution to the pathology is poorly understood. Our objective was to investigate maternal systemic immune changes in early-onset PE (EOPE) and late-onset PE (LOPE) vs uncomplicated pregnancies (CTRL), and their contribution to endothelial activation, hallmark of hypertension. Blood samples were analyzed by flow cytometry, multiplex assay, intracellular cytokine staining (ICS), and single-cell RNA sequencing. We performed co-cultures between circulating immune cells and human umbilical veins endothelial cells (HUVECs) to assess endothelial activation. We found that EOPE had decreased Treg (4.64±0.33, p<0.05) and monocytes (33.92±3.08, p<0.01), whereas LOPE had decreased Treg (4.60±0.30, p<0.05) and Th2 cells (7.50±0.62, p<0.01) vs CTRL. Compared to CTRL, elevated cytokines/chemokines, and growth factors were observed in LOPE, whereas EOPE primarily showed decreased levels. Using ICS, we observed more monocytes producing IL-12, TNF, and IL-1 (all p<0.05) in LOPE vs CTRL. At the transcriptomic level, we found differentially expressed genes (DEGs) between EOPE and CTRL, predominantly related to upregulation of immune activation pathways. Lastly, EOPE peripheral blood mononuclear cells (PBMCs) induced heightened endothelial activation in vitro observed by increased ICAM-1 and ET-1 (p<0.05), whereas LOPE PBMCs required LPS stimulation. While significant proteomic changes are observed in the LOPE group, the EOPE displayed changes mostly at the transcriptomic levels and could induce endothelial activation in vitro.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266488 | GEO | 2024/09/24

REPOSITORIES: GEO

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Project description:Hypertension in pregnancy is the leading cause of morbidity and mortality in pregnancy, affecting up to 10% of all gestations1. Hypertensive disorders of pregnancy include chronic hypertension, gestational hypertension, eclampsia and pre-eclampsia, all of which increase the risk of complications in both mothers and babies during gestation. Preeclampsia, in particular, is characterised by the new-onset of gestational hypertension in the presence of proteinuria or other organ damage. It affects 5-7% of pregnancies and causes approximately 76,000 maternal deaths and 500,000 foetal deaths worldwide each year2. The classification of preeclampsia has been evolving over the last decade. In 2013, American College of Obstetricians and Gynecologists (ACOG) and International Society for the Study of Hypertension in Pregnancy (ISSHP) in the absence of proteinuria included other symptoms/features including liver dysfunction, thrombocytopenia, cerebrovascular events or foetal growth restriction (FGR) in the diagnosis of preeclampsia 1,3,4. Despite the fact that preeclampsia is a multifactorial and heterogeneous disorder, it is now widely accepted that preeclampsia is stratified depending on the time of onset into: i) early-onset PE (EOPE) manifested before 34 weeks of gestation, and ii) late-onset PE (LOPE) manifested from 34 weeks of gestation. Although EOPE and LOPE share the same diagnostic criteria, these two phenotypes of preeclampsia lead to different outcomes. EOPE is commonly associated with FGR, abnormal uterine artery Doppler often leading to preterm birth and higher risk of post-pregnancy morbidities5,6. On the other hand, LOPE appears to be a less severe disorder, often with normal or slightly increased uterine resistance index and a low rate of FGR6,7. Distinct delineation between EOPE and LOPE is still not well understood, with most patients with preeclampsia presenting elements of both pathologies proposing a clinical spectrum for preeclampsia. The lack of untargeted discovery studies involving ‘omics’ analyses has impeded understanding of the molecular differences between these two phenotypes of preeclampsia. Notably, a study from 20058 utilised a proteomics approach using urine samples from a cohort of pregnant women with EOPE and healthy controls, however the differences between EOPE and LOPE were not elucidated. Another more recent bioinformatics study, identified overlapping pathogenic mechanisms between preeclampsia, hypertension and heart disease but could not stratify between EOPE and LOPE due to underreported of data related to individual phenotypes9. In this study, we conducted an unbiased, comprehensive proteomics investigation using plasma samples collected from patients with EOPE (n=17) and LOPE (n=11), compared with age- and BMI-matched normotensive controls (n=18). The use of plasma samples is able to better reflect the pathogenesis of EOPE and LOPE as systemic conditions centred by widespread endothelial dysfunction.

Project description:Background: Early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE) has been regarded as two different phenotypes with heterogeneous manifestation. The underlying mechanisms remain elusive. Aim to gain insight into the pathogenesis of the two traits, we analyzed the placental gene expression profiles in preeclampsia placentas. Methods: Whole genome-wide microarray was used to describe the gene expression profiles in the placenta tissues from patients with early-(n=7; <34 weeks), late-onset(n=8; >36 weeks) PE and their controls who delivered preterm (n=5;<34 weeks) or at term(n=5; >36 weeks) Genes were selected as differentially expressed upon a fold-changeâ?¥2 and q-value<0.05. qRT-PCR was undertaken to verify the results. Western blot was further performed to verify secreted genes at the protein level. Results: A total of 627 genes were differentially expressed in early-compared with late-onset PE. Of these, 177 genes were up-regulated and 450 genes down-regulated in early-onset PE. Go analysis showed significant alteration in several biological processes, in addition to the processes which have been found before, such as immune and inflammatory response, cell adhension, female pregnancy and blood vessel development. We also found alteration in G-protein coupled receptor protein signaling pathway, G protein-coupled receptor 124 (GPR124) (P=0.0064) and MAS-related GPR, member F (MRGPRF)(P=0.0155 ) were both down-regulated obviously in early-onset PE. Conclusion: The different gene expression profiles suggested early- and late-onset PE are separate disease entities. Moreover, G-protein coupled receptor protein signaling pathway may contribute to the mechanism underlying early- and late-onset preeclampsia. Whole genome-wide microarray was used to describe the gene expression profiles in the placenta tissues from patients with early-(n=7; <34 weeks), late-onset (n=8; >36 weeks) PE and their controls who delivered preterm(n=5;<34 weeks) or at term(n=5; >36 weeks). Pooled controls who delivered at term were labled with cy5.

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Circulating immune cells from early- and late-onset preeclampsia displays distinct profiles with differential impact on endothelial activation

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