Pathophysiology Of Preeclampsia Research Articles

MECHANISMS OF EPIGENETIC REGULATION IN THE DEVELOPMENT OF PREECLAMPSIA

Introduction. The etiology and pathophysiology of pre-eclampsia (PE) are unclear. Effective methods of its prognosis, prevention and treatment have not still been devised. Of great interest have been the prospects for the use microRNA molecules that epigenetically control the expression of target genes at the post-transcriptional level and of key importance in proliferation, differentiation, invasion, migration, apoptosis of trophoblast cells, regulation of angiogenesis, immune response and other processes which occur during pregnancy Aim. The objective of the study is to investigate the epigenetic development mechanisms of PE based on the evaluation of the expression of pathogenetically significant microRNAs in women’s blood plasma. Materials and methods. The study include 62 female patients divided into the main study group (42 pregnant women with PE) and the control group (20 healthy women with uncomplicated pregnancy, childbirth and post-natal period). All patients have undergone a general clinical, laboratory, instrumental examination. The expression 15 micRroNAs level in blood plasma has been evaluated using a quantitative real-time polymerase chain reaction.The software DIANA miRPath v. 3.0 has been used to evaluate the effect of differentially expressed microRNAs on the signalling pathways functioning . The statistical data processing has been carried out using the licensed software package Statistica 6.0. Results. The women with PE have been detected to have multidirectional changes in the expression of 13 out of 15 plasma microRNAs compared with the control group; however, there has been a statistically significant decrease in the expression levels of 8 microRNAs: hsa-miR-146a-5p, hsa-miR-181a-5p , hsa-miR-210-3p, hsa-miR-517a-3p , hsa-miR-517c-3p, hsa-miR-574-3p, hsa-miR-574-5p, hsa-miR-1304-5p . The subgroup of pregnant women having PE proceeding with the symptoms of fetal growth retardation (FGR), has shown a significant decrease in the expression of hsa-miR-20a-5p and hsa-miR-143-3p molecules compared with the subgroup without FGR. Dysregulation of more than 40 signalling pathways has been shown. Conclusion. The development of PE proceeds alongside with significant epigenetic changes accompanied by changes in the microRNA expression profile which are associated with cardiovascular, cerebrovascular diseases, placental disorders. The detected differentially expressed microRNAs may be potential diagnostic markers of PE

Histopathologic Changes in the Placenta of Pregnant Women with Preeclampsia

Objective: The placenta plays a key role in the development of pre-eclampsia. Knowledge of the histopathologic changes in the preeclamptic placenta will improve our understanding of the pathophysiology of preeclampsia, which may contribute to the development of timely interventions, prevention strategies or treatment options. Therefore, in this study, we investigated the histopathologic changes in the placentas of pre-eclampsia patients. Material and Methods: This study was conducted between May 01, 2023, and January 31, 2024, at tertiary hospital. A total of 30 pregnancies were included in the study, 15 with preeclampsia and 15 that were otherwise normal pregnancies. After delivery by cesarean section, the placentas of these patients were taken to the Department of Histology and Embryology examined histologically by staining with hematoxylin-eosin. Results: Compared to the control group, the placentas of the pre-eclampsia patients showed a more degeneration of the villi, hemorrhage in the intervillous area, the presence of immune cells, vasodilation, and congestion. In addition, there were more fibrinoid accumulations and more syncytial knots in the placentas of the pre-eclampsia patients. Conclusion: There were histologic differences between the placenta of pre-eclampsia patients and the control group. The studies that search the precursor markers leading to these histopathologic changes are necessary to improve our understanding of preeclampsia and to develop further strategies such as treatment options and prevention strategies. Keywords: Preeclampsia, hematoxylin-eosin staining, histopathologic examination

Assessment of High Serum Cystatin C as an Early Marker of Renal Impairment in Pre Eclampsia

Introduction: Preeclampsia is the most common medical complication during pregnancy and one of the leading causes of maternal and perinatal morbidity and mortality in Bangladesh. Kidney has role in both adaptive physiology of normal pregnancy and in pathophysiology of preeclampsia. Among the new biomarkers, serum Cystatin C can reliably reflect the GFR in both healthy and hypertensive pregnant women. It is important to evaluate the diagnostic efficiency of Cystatin C as a marker of renal function in preeclampsia. Aim: To assess high serum Cystatin C level as an early marker of renal impairment in pre-eclamptic patients. Materials and Methods: From March, 2021 to February, 2022 (A total of 12 months) a cohort study was conducted among 66 pregnant women, aged 18 to 40 years with pre-eclampsia and normal serum creatinine (0.5-0.8mg/dl) at their 20-28 weeks of gestation attending the antenatal clinic and admitted in the Department of Feto maternal Medicine, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, selected by non random purposive and convenient sampling. Results: Out of 66 respondents, final analysis was done with 62 patients. Among 62 study samples, 76% patients had “High Cystatin C” level that was greater than 0.84 and renal impairment developed in 15% pregnant women. Majority of the participants were in 25-30 age groups (46.8%). The mean serum creatinine level of the pregnant women increased throughout follow up and it was statistically significant (p<0.05) in both cases. No significant difference was found between serum Cystatin C in renal impaired and normal renal function pre eclampsia patients at a cut off value of 0.84. ROC analysis of serum Cystatin C level for detection of renal impairment among Pre eclamptic patients found a cut-off value of ≥1.49 showed the highest Youden index of 0.721. The sensitivity, specificity, PPV, NPV and accuracy of serum Cystatin C were 77.78%, 94.34%, 70.00%, 96.15% and 91.94%. Conclusion: Higher Cystatin C level in pre-eclampsia reflected renal impairment at an early stage even before conventional marker like serum creatinine raise. The diagnostic efficiency of Cystatin C as a marker of renal function in pre eclampsia can be used to reduce maternal morbidity and mortality of Bangladesh. Medicine Today 2023 Vol.36 (1): 12-16

Understanding the Pathophysiology of Preeclampsia: Exploring the Role of Antiphospholipid Antibodies and Future Directions.

Preeclampsia (PE) is a hypertensive disorder in pregnancy associated with significant fetal and maternal complications. Antiphospholipid syndrome (APS) is an acquired form of thrombophilia characterized by recurrent venous or arterial thrombosis and obstetric complications that significantly increases morbidity and mortality rates. While preeclampsia may not be the most prevalent obstetric complication in APS, it significantly impacts the long-term health of both mother and child. The treatment of preeclampsia in antiphospholipid syndrome is different from the treatment of preeclampsia as an independent disease. Despite current treatments involving anticoagulants, antiplatelet agents, and antihypertensive drugs, obstetric complications may persist, underscoring the need for cohesive management and effective treatments. The objective of our review is to briefly present knowledge about the physiopathology of preeclampsia and the role of antiphospholipid antibodies in this process. Based on the existing literature, our review aims to identify future directions in molecular pathology toward the discovery of biomarkers and targeted treatments. The application of multidisciplinary approaches and prognostic models, including new biomarkers, could be beneficial in the prediction of PE.

Vascular Endothelial Mitochondrial Oxidative Stress in Response to Placental Macrophages from Preeclamptic Pregnancies

Preeclampsia (PE), a hypertensive disorder of pregnancy characterized by maternal hypertension, fetal growth restriction (FGR), and chronic immune activation and inflammation, is a major cause of maternal and fetal morbidity and mortality worldwide. Prior clinical studies demonstrate that proinflammatory M1 macrophages are increased in women with PE. We do not understand the role that M1 macrophage polarization may play in PE pathophysiology. We set out to begin characterization of macrophages in patient samples obtained from the UMMC biobank and their ability to induce mitochondrial oxidative stress (ROS) in human umbilical vein endothelial cells (HUVECs). After obtaining informed consent, whole blood and placental tissues were collected from normal pregnant (n=5) and preeclamptic women (n=8) who delivered in the labor and delivery unit UMMC. Lymphocytes were isolated from blood on a Ficoll-Histopaque gradient and analyzed by flow cytometry for total and M1 macrophages. Total macrophages were isolated from digested placental tissue by magnetic bead separation using the Human Macrophage Isolation Kit (Miltenyi). Isolated macrophages were co-cultured with HUVECs overnight. After removal of culture inserts containing macrophages, HUVECs were serum-starved and incubated with MitoSox Red, collected, and analyzed on a flow cytometer. Total circulating macrophages were increased in placentas from PE women vs normal pregnant patients (10.8% PMBCs vs. 3.5% PMBCs, respectively, p<0.05). Furthermore, macrophage polarization to M1 macrophages was significantly higher in women with PE (15.02% of total macrophages) compared to NP women (6.23% of total macrophages, p<0.05 vs. PE). We also determined that mitochondrial ROS production was significantly elevated in HUVEC cells co-cultured with macrophages from PE pregnancies (15.37 A.U.) when compared to HUVECs co-cultured with normal pregnant control macrophages (7.788 A.U., p<0.05 vs. PE). Future studies will include enrollment of additional participants and determination of endothelial activation by measurement of adhesion molecules, growth factors, extracellular matrix proteins, and cytokines in HUVECs and conditioned media via Western Blot, ELISA, and multiplex analysis. These data show that PE placental macrophages induce mitochondrial ROS production in endothelial cells and may play a role to directly induce vascular dysfunction contributing to hypertension during a preeclamptic pregnancy. This work was supported by National Institutes of Health Grants T32HL105324 to C. A. Shields, and R01HL151407 to D. C. Cornelius. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Oxidative stress contributes to hypermethylation of Histone H3 lysine 9 in placental trophoblasts from preeclamptic pregnancies.

Aberrant epigenetic regulation and increased oxidative stress in the placenta play a significant role in placental pathophysiology and fetal programming in preeclampsia, a hypertensive disorder in human pregnancy. The purpose of the study is to investigate if hypermethylation of histone H3K9 occurs in placental trophoblasts from preeclampsia. Trophoblasts were isolated and cultured from 14 placentas, 7 from normotensive pregnant women and 7 from preeclamptic pregnancies. Methylated H3K9 expression and antioxidant superoxide dismutase expression were determined by Western blot. We also examined consequences of oxidative stress and the downstream effects of histone methyltransferase inhibition on H3K9 expression associated with antioxidant CuZn-SOD and Mn-SOD expression in placental trophoblasts. We found that expression of mono-, di-, and tri-methylation of histone H3 lysine 9 (H3K9me1, H3K9me2 and H3K9me3) was significantly increased, p<0.01, which correlated with downregulation of antioxidant superoxide dismutase CuZn-SOD and Mn-SOD expression, in trophoblasts from preeclamptic placentas compared to those from uncomplicated control placentas. We further demonstrated hypoxia could promote histone H3K9 methylation in placental trophoblasts, and hypoxia-induced upregulation of H3K9me1, H3K9me2 and H3K9me3 expression was reversible when hypoxic condition was removed. In addition, we also uncovered that inhibition of methyltransferase not only prevented hypoxia-induced upregulation of H3K9me1, H3K9me2 and H3K9me3 expression, but also abolished hypoxia-induced downregulation of CuZn-SOD and Mn-SOD expression in placental trophoblasts. These findings are noteworthy and provide further evidence that increased oxidative stress in the intrauterine environment is likely a mechanism to induce aberrant histone modification in placental trophoblasts in preeclampsia. Moreover, CuZn-SOD and Mn-SOD expression/activity are possibly H3K9 methylation-dependent in placental trophoblasts, which further suggest that oxidative stress and aberrant histone modification have significant impact on placental trophoblasts/fetal programming in preeclampsia.

PROTEIN SOLUBLE SUPPRESSION OF TUMORIGENICITY 2 (sST2) SEBAGAI PENANDA KERUSAKAN KARDIOVASKULAR PADA PREEKLAMSIA

Preeclampsia as a pregnancy complication was still a direct cause of maternal death, especially in developing countries. The process of abnormal trophoblast invasion as a pathophysiology of preeclampsia would cause an ischemic environment in the placenta. This situation caused the placenta to release pro-inflammatory cytokines and anti-angiogenic factors into the maternal circulation, resulting in the vasocontriction of blood vessels, endothelial dysfunction in the vasculature of maternal organs, and the production of different clinical features depending on the organs affected. Vascular and myocardial muscle damage was a complication that causes cardiovascular disorders and could increase maternal morbidity and mortality in preeclampsia. sST2 as part of the interleukin (IL)-1 receptor, was a biomarker used to indicate myocardial muscle damage in cardiac disease. There had been a growing number of research investigating the use of sST2 as a marker of cardiac muscle damage in patients with heart failure. Some of them concluded that sST2 can be used as a predictor of acute cardiac muscle damage. Others stated that sST2 as a marker could accompany chronic cardiac defects. Preeclampsia, as a disease in pregnancy that showed damage to maternal organs, was starting to be studied using this biomarker as a marker for damages to the cardiac organ. There were studies that showed differences in sST2 levels in preeclampsia with and without complications. Preeclampsia with cardiac complications was characterized by damage to the myocardial muscle, especially to the left ventricular area. The sST2 protein was starting to be used as a marker for this damage. Further research was still being carried out to improve the use of this biomarker as a marker for other damage to the maternal cardiac organ.

MicroRNA analysis of medium/large placenta extracellular vesicles in normal and preeclampsia pregnancies.

Preeclampsia (PE) is a hypertensive disorder of pregnancy, affecting 2%-8% of pregnancies worldwide, and is the leading cause of adverse maternal and fetal outcomes. The disease is characterized by oxidative and cellular stress and widespread endothelial dysfunction. While the precise mechanisms are not entirely understood, the pathogenesis of PE is closely linked to placental dysfunction and, to some extent, syncytiotrophoblast extracellular vesicle release (STB-EVs). These vesicles can be divided into the less well-studied medium/large EVs (220-1,000 nm) released in response to stress and small EVs (<220 nm) released as a component of intercellular communication. The previously described production of m/lSTB-EVs in response to cellular stress combined with the overwhelming occurrence of cellular and oxidative stress in PE prompted us to evaluate the microRNAome of PE m/lSTB-EVs. We hypothesized that the microRNAome profile of m/lSTB-EVs is different in PE compared to normal pregnancy (NP), which might permit the identification of potential circulating biomarkers not previously described in PE. We performed small RNA sequencing on medium/large STB-EVs isolated from PE and NP placentae using dual-lobe ex vivo perfusion. The sequencing data was bioinformatically analyzed to identify differentially regulated microRNAs. Identified microRNAs were validated with quantitative PCR analysis. We completed our analysis by performing an in-silico prediction of STB-EV mechanistic pathways. We identified significant differences between PE and NP in the STB-EVs micro ribonucleic acid (microRNA) profiles. We verified the differential expression of hsa-miR-193b-5p, hsa-miR-324-5p, hsa-miR-652-3p, hsa-miR-3196, hsa-miR-9-5p, hsa-miR-421, and hsa-miR-210-3p in the medium/large STB-EVs. We also confirmed the differential abundance of hsa-miR-9-5p in maternal serum extracellular vesicles (S EVs). In addition, we integrated the results of these microRNAs into the previously published messenger RNA (mRNA) data to better understand the relationship between these biomolecules. We identified a differentially regulated micro-RNA, hsa-miR-9-5p, that may have biomarker potential and uncovered mechanistic pathways that may be important in the pathophysiology of PE.

A Comprehensive Review on Serum Lactate Dehydrogenase (LDH) and Uric Acid in Preeclampsia: Implications for Maternal Health and Disease Severity.

Preeclampsia, a hypertensive disorder unique to pregnancy, remains a significant cause of maternal and fetal morbidity and mortality worldwide. Serum lactate dehydrogenase (LDH) and uric acid have garnered attention as potential biomarkers in understanding preeclampsia's pathophysiology and clinical management. Elevated LDH and uric acid levels have been associated with disease severity and adverse outcomes, highlighting their potential utility in risk stratification and guiding management strategies. This comprehensive review explores the roles of LDH and uric acid in preeclampsia, summarizing current evidence regarding their diagnostic, prognostic, and therapeutic implications. Future research directions are also discussed, including understanding and validation studies. Integrating LDH and uric acid measurements into routine clinical practice may facilitate early detection and intervention, ultimately improving outcomes for preeclamptic pregnancies. This review underscores the importance of serum biomarkers in enhancing our understanding and managing preeclampsia, aiming to optimize maternal and fetal health.

Fetal anemia causes placental and maternal cellular damage: a lesson from fetal hemoglobin Bart's disease

IntroductionThe studies about effect of fetal anemia on placental and maternal molecular changes have rarely been published. This study aimed to compare oxidative stress levels and mitochondrial function in the placenta and maternal peripheral blood mononuclear cell (PMBCs) between anemic fetuses (using fetal Hb Bart's disease as a study model) and non-anemic fetuses. MethodsA cross-sectional study was conducted on pregnancies affected by Hb Bart's disease and non-anemic fetuses between 16 and 22 weeks of gestation. Placental tissue and maternal blood for PBMCs were collected after pregnancy termination for determination of oxidative stress and mitochondrial function. ResultsA total of 18 pregnancies affected by Hb Bart's disease and 12 non-anemic fetuses were enrolled. Placental thickness was significantly greater (p-value <0.001) in the affected pregnancies, whereas all Doppler indices of uteroplacental blood flow were comparable. Mitochondrial dysfunction was significantly increased (p-value <0.001) in the placenta of the affected fetuses. In the mothers of affected fetuses, there was an increase in mitochondrial oxidative stress levels with a significant increase in mitochondrial dysfunction in isolated PBMCs (p-value <0.001). DiscussionIn the presence of normal uteroplacental Doppler studies, fetal anemia can induce a significant increase in oxidative stress and mitochondrial dysfunction in the placentas and mothers. The findings support that the placenta can be a source of oxidative stress agents which are released into systemic circulation prior to development of maternal adverse outcomes, and may explain pathophysiology of subsequent preeclampsia in late gestation, as commonly seen in pregnancies affected by fetal Hb Bart's disease, if pregnancy is not terminated.

Evaluating mean platelet volume and platelet distribution width as predictors of early-onset pre-eclampsia: a prospective cohort study

BackgroundPlatelets are pivotal players in the pathophysiology of pre-eclampsia, with observed lower counts in affected individuals compared to normotensive counterparts. Despite advancements, the elusive cause of pre-eclampsia persists, motivating intense global efforts to identify reliable predictors. The currently recommended predictors of pre-eclampsia are not readily available in many resource-limited regions like Nigeria. This cohort study explores the potential of mean platelet volume (MPV) and platelet distribution width (PDW) as predictive markers of early-onset pre-eclampsia. Both platelet indices are components of the full blood count, a widely available routine test in pregnancy.MethodsIn this prospective cohort study, 648 healthy pregnant women attending antenatal care at Lagos State University Teaching Hospital and General Hospital Ifako-Ijaiye, Lagos, were recruited between 14-18weeks gestational age. Platelet count (PC), MPV and PDW were measured from their venous blood at recruitment. Participants were monitored until 34weeks of gestation, focusing on the occurrence of early-onset preeclampsia as the outcome of interest. Individuals with chronic medical conditions were excluded from the study. Data analysis involved t-test, Chi-Square and Mann–Whitney U tests, with statistical significance set at a confidence level of 95% and p < 0.05. Sensitivity, specificity, and predictive values were determined using receiver operating characteristics (ROC) curves.ResultsThe incidence of early-onset pre-eclampsia in the study was 5.9%. Women who later developed pre-eclampsia had higher median MPV and PDW at 14-18weeks (10.8 fl. and 24.8 fl.) compared to normotensive women (8.1 fl. and 13.3 fl.)(p < 0.001). The median PC was lower in pre-eclamptics (190 × 103/µl) compared to normotensives(264 × 103/µl)(p < 0.001). Using Youden’s test, cut-off values identified: PC < 211.5 × 103/µl, MPV > 9.4 fl., and PDW > 21.3 fl., predicted early-onset pre-eclampsia with 96.6% sensitivity and 65.6% specificity for PC; 79.3% sensitivity and 97.7% specificity for PDW; and 82.8% sensitivity and 96.1% specificity for MPV. Cut-offs of PC < 185 × 103/µl, MPV > 10.7 fl., and PDW > 28.3 fl., predicted severe early-onset pre-eclampsia with 100.0% sensitivity and 90.9% specificity for PC, 100.0% sensitivity and 99.4% specificity for MPV, and 100.0% sensitivity and 99.8% specificity for PDW, with corresponding area under the ROC curves of 0.983, 0.996, and 0.998, respectively.ConclusionThe evaluation of MPV and PDW between 14 and 18 weeks of gestation appears to be a reliable predictor of severe early-onset pre-eclampsia.

Immunological regulation and the role of autophagy in preeclampsia.

Autophagy is a bulk degradation system that maintains cellular homeostasis by producing energy and/or recycling excess proteins. During early placentation, extravillous trophoblasts invade the decidua and uterine myometrium, facing maternal immune cells, which participate in the immune suppression of paternal and fetal antigens. Regulatory T cells will likely increase in response to a specific antigen before and during early pregnancy. Insufficient expansion of antigen-specific Treg cells, which possess the same T cell receptor, is associated with the pathophysiology of preeclampsia, suggesting sterile systemic inflammation. Autophagy is involved in reducing inflammation through the degradation of inflammasomes and in the differentiation and function of regulatory T cells. Autophagy dysregulation induces protein aggregation in trophoblasts, resulting in placental dysfunction. In this review, we discuss the role of regulatory T cells in normal pregnancies. In addition, we discuss the association between autophagy and regulatory T cells in the development of preeclampsia based on reports on the role of autophagy in autoimmune diseases.

Differences in Cardiometabolic Proteins in Pregnancy Prioritize Relevant Targets of Preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy characterized by widespread vascular inflammation. It occurs frequently in pregnancy, often without known risk factors, and has high rates of maternal and fetal morbidity and mortality. Identification of biomarkers that predict preeclampsia and its cardiovascular sequelae before clinical onset, or even before pregnancy, is a critical unmet need for the prevention of adverse pregnancy outcomes. We explored differences in cardiovascular proteomics (Olink Explore 384) in 256 diverse pregnant persons across 2 centers (26% Hispanic, 21% Black). We identified significant differences in plasma abundance of markers associated with angiogenesis, blood pressure, cell adhesion, inflammation, and metabolism between individuals delivering with preeclampsia and controls, some of which have not been widely described previously and are not represented in the preeclampsia placental transcriptome. While we observed a broadly similar pattern in early (<34 weeks) versus late (≥34 weeks) preeclampsia, several proteins related to hemodynamic stress, hemostasis, and immune response appeared to be more highly dysregulated in early preeclampsia relative to late preeclampsia. These results demonstrate the value of performing targeted proteomics using a panel of cardiovascular biomarkers to identify biomarkers relevant to preeclampsia pathophysiology and highlight the need for larger multiomic studies to define modifiable pathways of surveillance and intervention upstream to preeclampsia diagnosis.

First-trimester preterm preeclampsia prediction model for prevention with low-dose aspirin.

Preeclampsia (PE) is a major maternal and fetal threat. Previous risk-scoring methods in guidelines lacked precision. The Fetal Medicine Foundation (FMF) proposed a first-trimester PE screening model using Bayes' theorem. FMF prediction model combines maternal characteristics and medical/obstetrical history to determine prior risk and further incorporate maternal blood pressure, maternal serum biomarkers, and uterine Doppler pulsatility index expressed as multiples of the median (MoM) to estimate posterior risk. Low-dose aspirin is one ofthe potential PE prevention strategies. Initiating it before 16 weeks is crucial. Aspirin's antiplatelet and anti-inflammatory properties align with PE's pathophysiology. Dosing and resistance warrant further study, but a standard regimen of 150 mg nightly, starting before 16 weeks, is widely supported. Clinical trials, including ASPRE, affirm aspirin's role in PE prevention. Starting aspirin based on FMF screening significantly reduces preterm PE and associated complications. Emerging research explores predictors like maternal ophthalmic arterial waveform. Regional variations, especially in Asian populations, are considered. Machine learning and AI show promise, but examiner expertise remains essential for accurate prediction. In conclusion, integrating FMF's first-trimester PE screening with low-dose aspirin offers a promising strategy. Further advancements may enhance precision and broaden prevention efforts.

Differential 5'-tRNA Fragment Expression in Circulating Preeclampsia Syncytiotrophoblast Vesicles Drives Macrophage Inflammation.

The relationship between placental pathology and the maternal syndrome of preeclampsia is incompletely characterized. Mismatch between placental nutrient supply and fetal demands induces stress in the syncytiotrophoblast, the layer of placenta in direct contact with maternal blood. Such stress alters the content and increases the release of syncytiotrophoblast extracellular vesicles (STB-EVs) into the maternal circulation. We have previously shown 5'-tRNA fragments (5'-tRFs) constitute the majority of small RNA in STB-EVs in healthy pregnancy. 5'-tRFs are produced in response to stress. We hypothesized STB-EV 5'-tRF release might change in preeclampsia. We perfused placentas from 8 women with early-onset preeclampsia and 6 controls, comparing small RNA expression in STB-EVs. We used membrane-affinity columns to isolate maternal plasma vesicles and investigate placental 5'-tRFs in vivo. We quantified 5'-tRFs from circulating STB-EVs using a placental alkaline phosphatase immunoassay. 5'-tRFs and scrambled RNA controls were added to monocyte, macrophage and endothelial cells in culture to investigate transcriptional responses. 5'-tRFs constitute the majority of small RNA in STB-EVs from both preeclampsia and normal pregnancies. More than 900 small RNA fragments are differentially expressed in preeclampsia STB-EVs. Preeclampsia-dysregulated 5'-tRFs are detectable in maternal plasma, where we identified a placentally derived load. 5'-tRF-Glu-CTC, the most abundant preeclampsia-upregulated 5'-tRF in perfusion STB-EVs, is also increased in preeclampsia STB-EVs from maternal plasma. 5'-tRF-Glu-CTC induced inflammation in macrophages but not monocytes. The conditioned media from 5'-tRF-Glu-CTC-activated macrophages reduced eNOS (endothelial NO synthase) expression in endothelial cells. Increased release of syncytiotrophoblast-derived vesicle-bound 5'-tRF-Glu-CTC contributes to preeclampsia pathophysiology.

IL-33 supplementation improves uterine artery resistance and maternal hypertension in response to placental ischemia.

Preeclampsia (PE), a leading cause of maternal/fetal morbidity and mortality, is a hypertensive pregnancy disorder with end-organ damage that manifests after 20 wk of gestation. PE is characterized by chronic immune activation and endothelial dysfunction. Clinical studies report reduced IL-33 signaling in PE. We use the Reduced Uterine Perfusion Pressure (RUPP) rat model, which mimics many PE characteristics including reduced IL-33, to identify mechanisms mediating PE pathophysiology. We hypothesized that IL-33 supplementation would improve blood pressure (BP), inflammation, and oxidative stress (ROS) during placental ischemia. We implanted intraperitoneal mini-osmotic pumps infusing recombinant rat IL-33 (1 µg/kg/day) into normal pregnant (NP) and RUPP rats from gestation day 14 to 19. We found that IL-33 supplementation in RUPP rats reduces maternal blood pressure and improves the uterine artery resistance index (UARI). In addition to physiological improvements, we found decreased circulating and placental cytolytic Natural Killer cells (cNKs) and decreased circulating, placental, and renal TH17s in IL-33-treated RUPP rats. cNK cell cytotoxic activity also decreased in IL-33-supplemented RUPP rats. Furthermore, renal ROS and placental preproendothelin-1 (PPET-1) decreased in RUPP rats treated with IL-33. These findings demonstrate a role for IL-33 in controlling vascular function and maternal BP during pregnancy by decreasing inflammation, renal ROS, and PPET-1 expression. These data suggest that IL-33 may have therapeutic potential in managing PE.NEW & NOTEWORTHY Though decreased IL-33 signaling has been clinically associated with PE, the mechanisms linking this signaling pathway to overall disease pathophysiology are not well understood. This study provides compelling evidence that mechanistically links reduced IL-33 with the inflammatory response and vascular dysfunction observed in response to placental ischemia, such as in PE. Data presented in this study submit the IL-33 signaling pathway as a possible therapeutic target for the treatment of PE.

Deciphering the immunological interactions: targeting preeclampsia with Hydroxychloroquine's biological mechanisms.

Preeclampsia (PE) is a complex pregnancy-related disorder characterized by hypertension, followed by organ dysfunction and uteroplacental abnormalities. It remains a major cause of maternal and neonatal morbidity and mortality worldwide. Although the pathophysiology of PE has not been fully elucidated, a two-stage model has been proposed. In this model, a poorly perfused placenta releases various factors into the maternal circulation during the first stage, including pro-inflammatory cytokines, anti-angiogenic factors, and damage-associated molecular patterns into the maternal circulation. In the second stage, these factors lead to a systemic vascular dysfunction with consecutive clinical maternal and/or fetal manifestations. Despite advances in feto-maternal management, effective prophylactic and therapeutic options for PE are still lacking. Since termination of pregnancy is the only curative therapy, regardless of gestational age, new treatment/prophylactic options are urgently needed. Hydroxychloroquine (HCQ) is mainly used to treat malaria as well as certain autoimmune conditions such as systemic lupus and rheumatoid arthritis. The exact mechanism of action of HCQ is not fully understood, but several mechanisms of action have been proposed based on its pharmacological properties. Interestingly, many of them might counteract the proposed processes involved in the development of PE. Therefore, based on a literature review, we aimed to investigate the interrelated biological processes of HCQ and PE and to identify potential molecular targets in these processes.

Modern ideas about the mechanisms of development of preeclampsia

In recent years, the two-stage model of preeclampsia has been updated. The review examines modern ideas about the pathophysiology of preeclampsia. Particular attention is paid to studies of uterine artery remodeling, as well as the role of microRNAs in preeclampsia.

Inhibition of Caspase 1 Reduces Blood Pressure, Cytotoxic NK Cells, and Inflammatory T-Helper 17 Cells in Placental Ischemic Rats.

Preeclampsia (PE) is characterized by maternal hypertension, fetal growth restriction (FGR), and increased inflammation and populations of cytotoxic NK cells (cNKs) and inflammatory T-Helper 17 cells (TH17s). Both cytotoxic NK cells and TH17 cells are heavily influenced via IL-1β signaling. Caspase 1 activity leads to the release of the inflammatory cytokine IL-1β, which is increased in women with PE. Therefore, we tested the hypothesis that the inhibition of Caspase 1 with VX-765 in rats with reduced uterine perfusion pressure (RUPP) will attenuate PE pathophysiology. On gestation day (GD) 14, timed pregnant Sprague-Dawley rats underwent the RUPP or Sham procedure and were separated into groups that received either vehicle or VX-765 (50 mg/kg/day i.p.). On GD19, MAP was measured via carotid catheter and blood and tissues were collected. Bio-Plex and flow cytometry analysis were performed on placental tissues. Placental IL-1β was increased in the RUPP rats vs. the Sham rats and treatment with VX-765 reduced IL-1β in the RUPP rats. Caspase 1 inhibition reduced placental cNKs and TH17s in RUPP rats compared to vehicle-treated RUPP rats. Increased MAP was observed in RUPP rats compared with Sham rats and was reduced in RUPP + VX-765 rats. Placental reactive oxygen species (ROS) were elevated in RUPP rats compared to Sham rats. VX-765 administration reduced ROS in treated RUPP rats. Caspase 1 inhibition increased the number of live pups, yet had no effect on fetal weight or placental efficiency in the treated groups. In conclusion, Caspase 1 inhibition reduces placental IL-1β, inflammatory TH17 and cNK populations, and reduces MAP in RUPP rats. These data suggest that Caspase 1 is a key contributor to PE pathophysiology. This warrants further investigation of Caspase 1 as a potential therapeutic target to improve maternal outcomes in PE.

Pathophysiology of Preeclampsia

Preeclampsia is a hypertensive disease that occurs during pregnancy in 3 to 8% of pregnancies worldwide. This disease causes significant maternal and perinatal morbidity and mortality. This article attempts to understand the pathophysiological mechanism of preeclampsia, which appears to result from a complex interaction between maternal and fetal factors and affects multiple organ systems. A central role in pre-eclampsia appears to be abnormal placentation with subsequent excess of anti-angiogenic factors and malabsorption. Further studies are needed to elucidate the pathophysiology of preeclampsia to better understand the disease, more appropriate treatment, and reduce maternal and neonatal morbidity and mortality.