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Preeclampsia, a pregnancy-specific syndrome, poses substantial risks to maternal and neonatal health, particularly in cases with severe features. Our study focuses on evaluating the impact of low molecular weight metabolites on the intricate mechanisms and pathways involved in the pathophysiology of preeclampsia when severe features are present. We aim to pinpoint the distinct metabolomic profile in maternal plasma during pregnancies affected by hypertensive disorders and to correlate the metabolite levels with the clinical characteristics of the study cohort. A total of 173 plasma samples were collected, comprising 36 healthy pregnant women (HP), 52 patients with gestational hypertension (GH), 43 with preeclampsia without (PE–), and 42 with severe features (PE+). Nuclear magnetic resonance spectroscopy and metabolite identification were conducted to establish the metabolomic profiles. Univariate and chemometric analyses were conducted using MetaboAnalyst, and correlations were performed using GraphPad Prism. Our study unveils distinct metabolomic profiles differentiating HP women, patients featuring GH, and patients with PE–and PE+. Our analysis highlights an increase in acetate, N , N -dimethylglycine, glutamine, alanine, valine, and creatine levels in the PE+ group compared to the HP and GH groups. The PE+ group exhibited higher concentrations of N , N -dimethylglycine, glutamine, alanine, and valine compared to the PE–group. Moreover, elevated levels of specific metabolites, including N , N -dimethylglycine, alanine, and valine, were associated with increased blood pressure, worse obstetric outcomes, and poorer end-organ function, particularly renal and hepatic damage. Metabolomic analysis of PE+ individuals indicates heightened disturbances in nitrogen metabolism, methionine, and urea cycles. Additionally, the exacerbated metabolic disturbance may have disclosed renal impairment and hepatic dysfunction, evidenced by elevated levels of creatine and alanine. These findings not only contribute novel insights but also provide a more comprehensive understanding of the pathophysiological mechanisms at play in cases of PE+.

Hypertensive disorders of pregnancy (HDP), comprising gestational hypertension (GH) and pre-eclampsia (PE), are leading causes of maternal and perinatal morbidity and mortality. Both GH and PE are characterized by new-onset hypertension, but PE additionally includes proteinuria and/or end-organ damage. Impaired nitric oxide (NO) bioavailability may lead to endothelial dysfunction in GH and PE, and the primary source of vascular NO is endothelial NO synthase (eNOS). However, no previous study has investigated plasma eNOS concentrations in patients with GH and PE. In this study, we compared plasma eNOS concentrations in healthy pregnancies and HDP in two independent cohorts. The primary study included 417 subjects, with 43 non-pregnant (NP) and 156 healthy pregnant (HP) women and 122 patients with GH and 96 with PE. The replication study included 85 pregnant women (41 healthy and 44 pre-eclamptic). Plasma concentrations of eNOS were measured using a commercial ELISA kit provided by R&D Systems, and plasma nitrite concentrations were assessed using two ozone-based chemiluminescence assays. Correlations between plasma eNOS concentrations and plasma nitrite concentrations, as well as clinical and biochemical parameters, were evaluated by either Spearman’s or Pearson’s tests. In the primary study, NP women and HDP had significantly lower plasma eNOS concentrations compared to HP; concentrations were even lower in PE compared to GH. Plasma eNOS concentrations were reduced but not significant in early-onset PE, PE with severe features, preterm birth, and intrauterine growth restriction. No correlation was observed between plasma eNOS and nitrite levels. In HDP, there was a significant positive correlation between levels of eNOS and hemoglobin (r = 0.1496, p = 0.0336) as well as newborn weight (r = 0.1487, p = 0.0316). Conversely, a negative correlation between eNOS levels and proteinuria was observed (r = −0.2167, p = 0.0179). The replication study confirmed significantly reduced plasma concentrations of eNOS in PE compared to HP. Our findings provide evidence of reduced plasma eNOS concentrations in HDP; they were particularly lower in PE compared to GH and HP in two independent studies.

Preeclampsia (PE) is a hypertensive pregnancy syndrome associated with target organ damage and increased cardiovascular risks, necessitating antihypertensive therapy. However, approximately 40% of patients are nonresponsive to treatment, which results in worse clinical outcomes. This study aimed to compare circulating proteomic profiles and identify differentially expressed proteins among 10 responsive (R-PE), 10 nonresponsive (NR-PE) patients, and 10 healthy pregnant controls (HP). We also explored correlations between these proteins and clinical data. Plasma protein relative quantification was performed using mass spectrometry, followed by bioinformatics analyses with the UniProt database, PatternLab for Proteomics 4.0, and MetaboAnalyst software (version 6.0). Considering a fold change of 1.5, four proteins were differentially expressed between NR-PE and R-PE: one upregulated (fibronectin) and three downregulated (pregnancy-specific beta-1-glycoprotein 1, complement C4B, and complement C4A). Between NR-PE and HP, six proteins were differentially expressed: two upregulated (clusterin and plasmin heavy chain A) and four downregulated (apolipoprotein L1, heparin cofactor II, complement C4B, and haptoglobin-related protein). Three proteins were differentially expressed between R-PE and HP: one downregulated (transthyretin) and two upregulated (apolipoprotein C1 and hemoglobin subunit beta). These findings suggest a complex interplay of these proteins involved in inflammatory, immune, and metabolic processes with antihypertensive therapy responsiveness and PE pathophysiology.