ArticleReproductive sciences (Thousand Oaks, Calif.)2020
Proteases Activate Pregnancy Neutrophils by a Protease-Activated Receptor 1 Pathway: Epigenetic Implications for Preeclampsia.
Article in Reproductive sciences (Thousand Oaks, Calif.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 18 citations in OpenAlex.
- A meta-analysis on first-trimester blood count parameters-is the neutrophil-to-lymphocyte ratio a potentially novel method for first-trimester preeclampsia screening?Frontiers in medicine · 2024Pooled it
- Multiple analytical perspectives of mitochondrial genes in the context of preeclampsia: potential diagnostic markers.Frontiers in immunology · 2025Article
- Pan-Immune-Inflammation Value and Risk of Hypertensive Disorders of Pregnancy: A Cross-Sectional Study.Journal of inflammation research · 2025Article
- DNA methylation landscape in pregnancy-induced hypertension: progress and challenges.Reproductive biology and endocrinology : RB&E · 2024Review
- [Analysis of Risk Factors for Recurrent Pregnancy Loss in Patients UndergoingSichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · 2024Article
- The NFκB Signaling Pathway Is Involved in the Pathophysiological Process of Preeclampsia.Geburtshilfe und Frauenheilkunde · 2024Article
- Proteomic profile of extracellular vesicles in maternal plasma of women with fetal death.The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians · 2023Article
- Obesity Correlates with Chronic Inflammation of the Innate Immune System in Preeclampsia and HELLP Syndrome during Pregnancy.Biomedicines · 2023Article
- Methylation-based epigenetic studies and gene integration analysis of preeclampsia.Annals of translational medicine · 2022Article
- Low-dose aspirin therapy improves decidual arteriopathy in pregnant women with a history of preeclampsia.Virchows Archiv : an international journal of pathology · 2022Article
- Aspirin Inhibits the Inflammatory Response of Protease-Activated Receptor 1 in Pregnancy Neutrophils: Implications for Treating Women with Preeclampsia.International journal of molecular sciences · 2022Article
- Gene Expression of Pregnancy Neutrophils Differs for Protease versus Lipopolysaccharide Stimulation.International journal of molecular sciences · 2022Article
- Pregnancy-specific expression of protease-activated receptor 1: a therapeutic target for prevention and treatment of preeclampsia?American journal of obstetrics and gynecology · 2022Review
- Epigenetic Regulation of Interleukin-17-Related Genes and Their Potential Roles in Neutrophil Vascular Infiltration in Preeclampsia.Reproductive sciences (Thousand Oaks, Calif.) · 2022Article
- Cellular immune responses in the pathophysiology of preeclampsia.Journal of leukocyte biology · 2022Review
- Patterns of Maternal Neutrophil Gene Expression at 30 Weeks of Gestation, but Not DNA Methylation, Distinguish Mild from Severe Preeclampsia.International journal of molecular sciences · 2021Article
- The Road to Low-Dose Aspirin Therapy for the Prevention of Preeclampsia Began with the Placenta.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
We tested a novel hypothesis that elevated levels of proteases in the maternal circulation of preeclamptic women activate neutrophils due to their pregnancy-specific expression of protease-activated receptor 1 (PAR-1). Plasma was collected longitudinally from normal pregnant and preeclamptic women and analyzed for MMP-1 and neutrophil elastase. Neutrophils were isolated for culture and confocal microscopy. Omental fat was collected for immunohistochemistry. Circulating proteases were significantly elevated in preeclampsia. Confocal microscopy revealed that tet methylcytosine dioxygenase 2 (TET2), a DNA de-methylase, and p65 subunit of NF-κB were strongly localized to the nucleus of untreated neutrophils of preeclamptic women, but in untreated neutrophils of normal pregnant women they were restricted to the cytosol. Treatment of normal pregnancy neutrophils with proteases activated PAR-1, leading to activation of RhoA kinase (ROCK), which triggered translocation of TET2 and p65 from the cytosol into the nucleus, mimicking the nuclear localization in neutrophils of preeclamptic women. IL-8, an NF-κB-regulated gene, increased in association with TET2 and p65 nuclear localization. Co-treatment with inhibitors of PAR-1 or ROCK prevented nuclear translocation and IL-8 did not increase. Treatment of preeclamptic pregnancy neutrophils with inhibitors emptied the nucleus of TET2 and p65, mimicking the cytosolic localization of normal pregnancy neutrophils. Expression of PAR-1 and TET2 were markedly increased in omental fat vessels and neutrophils of preeclamptic women. We conclude that elevated levels of circulating proteases in preeclamptic women activate neutrophils due to their pregnancy-specific expression of PAR-1 and speculate that TET2 DNA de-methylation plays a role in the inflammatory response.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.