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Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 22526

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Dr. Agata Sakowicz

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Department of Medical Biotechnology, Medical University of Lodz, 93-558 Lodz, Poland
Interests: gestational hypertension

Special Issue Information

Dear Colleagues,

One of the main causes of maternal and fetal mortality and morbidity is pregnancy complicated by hypertension. Such hypertensive disorders affecting expectant women can be divided into the following categories depending on the time of identification: chronic hypertension, gestational hypertension, pre-eclampsia/eclampsia, and pre-eclampsia superimposed on chronic hypertension. It is believed that maternal, fetal, and placental factors influence the pathomechanisms of these diseases, especially those diagnosed after mid-gestation. However, there is currently a lack of extensive knowledge regarding the cellular pathways, molecular markers, and maternal or fetoplacental factors influencing the generation of hypertension during gestation. Moreover, although the diagnostic tests used to predict hypertension in gestation are becoming more effective, the preventive and pharmacological strategies remain to be improved.

All researchers and scientists studying the molecular mechanisms associated with the development of hypertension during pregnancy are encouraged to submit original and review papers. This Special Issue aims to promote clinical, in vitro, or in vivo studies that seek to determine the maternal and/or fetoplacental factors linked with pregnancy-induced hypertension, including pre-eclampsia/eclampsia. Papers examining new strategies for the diagnosis of high blood pressure after mid-gestation, as well as existing or potential strategies for the prevention and treatment of hypertension generated by pregnancy, will also be considered.

This special issue is supervised by Dr. Agata Sakowicz and assisted by Dr. Agnieszka Gach（The Head of the Genetic Department of the Polish Mother's Memorial Hospital-Research Institute).

Dr. Agata Sakowicz
Guest Editor

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Keywords

molecular markers
molecular pathway
pre-eclampsia
pregnancy-induced hypertension
treatment

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Published Papers (11 papers)

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14 pages, 900 KiB

Open AccessArticle

The Influence of Non-Dipping Pattern of Blood Pressure in Gestational Hypertension on Early Onset of Hypertension Later in Life—Single Center Experience in Very-High-Risk Southeast and Central European Country

by Aleksandra Ilić, Anastazija Stojšić-Milosavljević, Tatjana Miljković, Marija Bjelobrk, Snežana Stojšić, Snežana Tadić, Maja Stefanović, Aleksandra Vulin, Andrej Preveden, Nikola Komazec, Milenko Čanković, Milovan Petrović, Djordje Ilić, Lazar Velicki, Mila Kovačević, Dragana Grković and Aleksandra Milovančev

Int. J. Mol. Sci. 2024, 25(20), 11324; https://doi.org/10.3390/ijms252011324 - 21 Oct 2024

Viewed by 667

Abstract

Gestational hypertension (GH) and preeclampsia (PE) are associated with the onset of hypertension. This study aimed to investigate whether the blood pressure (BP) pattern in GH is associated with the prevalence of hypertension later in life. In this prospective cohort study pregnant women screened for GH underwent medical history, laboratory analysis, ambulatory blood pressure monitoring (AMBP), and transthoracic echocardiography (with left ventricular global longitudinal strain (LVGLS)) assessment. Overall, 138 GH (67 non-dippers and 71 dippers), 55 preeclamptic, and 72 normotensive pregnant controls were included. Women were followed in the postpartum period, first after 6 weeks and later on, for the occurrence of hypertension. The median follow-up was 8.97 years (8.23; 9.03). Non-dippers and PE compared with normotensives and dippers had a higher prevalence of hypertension onset (p < 0.01), as well as significantly reduced absolute values of LVGLS during pregnancy, after delivery, and at the time of onset of hypertension during follow-up (p < 0.01). Night-time diastolic BP, LVGLS, age, and left ventricular ejection fraction were the strongest predictors of postpartum onset of hypertension. The non-dipping BP pattern in GH was significantly associated with the onset of hypertension later in life, as well as with decreased systolic function. Full article

(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)

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16 pages, 2342 KiB

Open AccessArticle

Different Proteomic Profiles Regarding Antihypertensive Therapy in Preeclampsia Pregnant

by Caroline C. Pinto-Souza, Julyane N. S. Kaihara, Priscila R. Nunes, Moises H. Mastella, Bruno C. Rossini, Bruna Cavecci-Mendonça, Ricardo de Carvalho Cavalli, Lucilene D. dos Santos and Valeria C. Sandrim

Int. J. Mol. Sci. 2024, 25(16), 8738; https://doi.org/10.3390/ijms25168738 - 10 Aug 2024

Viewed by 1025

Abstract

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. Full article

(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)

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15 pages, 4265 KiB

Open AccessArticle

Immunological Profiling of CD8⁺ and CD8⁻ NK Cell Subpopulations and Immune Checkpoint Alterations in Early-Onset Preeclampsia and Healthy Pregnancy

by Laszlo Szereday, David U. Nagy, Fanni Vastag, Livia Mezosi and Matyas Meggyes

Int. J. Mol. Sci. 2024, 25(15), 8378; https://doi.org/10.3390/ijms25158378 - 31 Jul 2024

Viewed by 851

Abstract

Despite the numerous studies on the clinical aspects of early-onset preeclampsia, our understanding of the immunological consequences of inadequate placenta development remains incomplete. The Th1-predominance characteristic of early-onset preeclampsia significantly impacts maternal immunotolerance, and the role of immune checkpoint molecules in these mechanisms is yet to be fully elucidated. Our study aims to fill these crucial knowledge gaps. A total of 34 pregnant women diagnosed with early-onset preeclampsia and 34 healthy pregnant women were enrolled in this study. A mononuclear cell fragment from the venous blood was separated and frozen. The CD8⁺ and CD8⁻ NK cell subpopulations were identified and compared to their immune checkpoint molecule expressions using multicolor flow cytometry. The serum CD226 levels were measured by ELISA. Based on our measures, the frequency of the CD8⁻ subpopulation was significantly higher than that of the CD8⁺ counterpart in both the NKdim and NKbright subsets. Significantly lower CD226 surface expressions were detected in the preeclamptic group compared to healthy women in all the investigated subpopulations. However, while no difference was observed in the level of the soluble CD226 molecule between the two groups, the CD112 and CD155 surface expressions were significantly different. Our study’s findings underscore the significant role of the CD8⁺ and CD8⁻ NK subpopulations in the Th1-dominated immune environment. This deepens our understanding of early-onset preeclampsia and suggests that each subpopulation could contribute to the compensation mechanisms and the restoration of the immunological balance in this condition, a crucial step toward developing effective interventions. Full article

(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)

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20 pages, 6910 KiB

Open AccessArticle

Overexpression of Human sFLT1 in the Spongiotrophoblast Is Sufficient to Induce Placental Dysfunction and Fetal Growth Restriction in Transgenic Mice

by Rebekka Vogtmann, Alina Riedel, Ivanka Sassmannshausen, Sarah Langer, Elisabeth Kühnel-Terjung, Rainer Kimmig, Hubert Schorle, Elke Winterhager and Alexandra Gellhaus

Int. J. Mol. Sci. 2024, 25(4), 2040; https://doi.org/10.3390/ijms25042040 - 7 Feb 2024

Viewed by 1734

Abstract

Preeclampsia (PE) is characterized by maternal hypertension and placental dysfunction, often leading to fetal growth restriction (FGR). It is associated with an overexpression of the anti-angiogenic sFLT1 protein, which originates from the placenta and serves as a clinical biomarker to predict PE. To analyze the impact of sFLT1 on placental function and fetal growth, we generated transgenic mice with placenta-specific human sFLT1 (hsFLT1) overexpression. Immunohistochemical, morphometrical, and molecular analyses of the placentas on 14.5 dpc and 18.5 dpc were performed with a focus on angiogenesis, nutrient transport, and inflammation. Additionally, fetal development upon placental hsFLT1 overexpression was investigated. Dams exhibited a mild increase in serum hsFLT1 levels upon placental hsFLT1 expression and revealed growth restriction of the fetuses in a sex-specific manner. Male FGR fetuses expressed higher amounts of placental hsFLT1 mRNA compared to females. FGR placentas displayed an altered morphology, hallmarked by an increase in the spongiotrophoblast layer and changes in labyrinthine vascularization. Further, FGR placentas showed a significant reduction in placental glycogen storage and nutrient transporter expression. Moreover, signs of hypoxia and inflammation were observed in FGR placentas. The transgenic spongiotrophoblast-specific hsFLT1 mouse line demonstrates that low hsFLT1 serum levels are sufficient to induce significant alterations in fetal and placental development in a sex-specific manner. Full article

(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)

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16 pages, 4755 KiB

Open AccessArticle

Sodium Nitrite Attenuates Reduced Activity of Vascular Matrix Metalloproteinase-2 and Vascular Hyper-Reactivity and Increased Systolic Blood Pressure Induced by the Placental Ischemia Model of Preeclampsia in Anesthetized Rats

by Laisla Zanetoni Martins, Maria Luiza Santos da Silva, Serginara David Rodrigues, Sáskia Estela Biasotti Gomes, Laura Molezini, Elen Rizzi, Marcelo Freitas Montenegro and Carlos Alan Dias-Junior

Int. J. Mol. Sci. 2023, 24(16), 12818; https://doi.org/10.3390/ijms241612818 - 15 Aug 2023

Viewed by 1270

Abstract

Preeclampsia is a maternal hypertension disorder associated with vascular dysfunction and fetal and placental growth restrictions. Placental ischemia is suggested as the primary trigger of preeclampsia-associated impairments of both endothelium-derived nitric oxide (NO) and the vascular activity of extracellular matrix metalloproteinase-2 (MMP-2). Reduced uteroplacental perfusion pressure (RUPP) is a placental ischemia model of preeclampsia. Reduction of sodium nitrite to NO may occur during ischemic conditions. However, sodium nitrite effects in the RUPP model of preeclampsia have not yet been investigated. Pregnant rats were divided into four groups: normotensive pregnant rats (Norm-Preg), pregnant rats treated with sodium nitrite (Preg + Nitrite), preeclamptic rats (RUPP), and preeclamptic rats treated with sodium nitrite (RUPP + Nitrite). Maternal blood pressure and fetal and placental parameters were recorded. Vascular function, circulating NO metabolites, and the gelatinolytic activity of vascular MMP-2 were also examined. Sodium nitrite attenuates increased blood pressure, prevents fetal and placental weight loss, counteracts vascular hyper-reactivity, and partially restores NO metabolites and MMP-2 activity. In conclusion, sodium nitrite reduction to NO may occur during RUPP-induced placental ischemia, thereby attenuating increased blood pressure, fetal and placental growth restriction, and vascular hyper-reactivity associated with preeclampsia and possibly restoring NO and MMP-2 activity, which underlie the blood pressure-lowering effects. Full article

(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)

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18 pages, 2105 KiB

Open AccessArticle

The Impact of Hydroxychloroquine on Primary Feto-Placental Endothelial Cells from Healthy and Early-Onset Preeclamptic Placentas

by Maja Gajić, Bianca Schröder-Heurich, Monika Horvat Mercnik, Mila Cervar-Zivkovic, Christian Wadsack, Frauke von Versen-Höynck and Karoline Mayer-Pickel

Int. J. Mol. Sci. 2023, 24(13), 10934; https://doi.org/10.3390/ijms241310934 - 30 Jun 2023

Cited by 1 | Viewed by 1710

Abstract

Hydroxychloroquine (HCQ), an anti-malarial drug, is suggested as a promising candidate for the treatment of pregnancy-related disorders associated with endothelial activation, among which there is preeclampsia (PE). Arterial feto-placental endothelial cells (fpECAs) were isolated from control (CTR) and early-onset preeclamptic (EO-PE) placentas. The aim of this study was to test potential protective effects of HCQ in an in vitro model of endothelial activation as well as in cells isolated from EO-PE placentas. To mimic PE conditions, CTR fpECAs were exposed to a pro-inflammatory environment consisting of tumor necrosis factor α (TNF-α), interleukin (IL)-6 and IL-1β (furtherly referred as MIX) with or without varying concentrations of HCQ (1 µg/mL and 10 µg/mL). Their effect on wound healing and endothelial barrier integrity was analyzed. Variations in the expression of IL-8 and leukocyte adhesion molecules (LAM) on both mRNA and protein levels were determined between CTR and PE fpECAs in the presence or absence of HCQ. MIX decreased wound healing and stability of the endothelial barrier, but HCQ did not affect it. Significant differences between CTR and EO-PE fpECAs were observed in IL-8 mRNA, protein secretion, and vascular cell adhesion protein 1 (VCAM-1) mRNA expression levels. After challenging CTR fpECAs with MIX, upregulation of both mRNA and protein levels was observed in all molecules. Combined treatment of HCQ and MIX slightly lowered VCAM-1 total protein amount. In CTR fpECAs, treatment with low concentrations of HCQ alone (1 µg/mL) reduced basal levels of IL-8 and VCAM-1 mRNA and secretion of IL-8, while in EO-PE fpECAs, a higher (10µg/mL) HCQ concentration slightly reduced the gene expression of IL-8. Conclusion: These results provide additional support for the safety of HCQ, as it did not adversely affect endothelial functionality in control fpECAs at the tested concentration. Furthermore, the observed limited effects on IL-8 secretion in EO-PE fpECAs warrant further investigation, highlighting the need for clinical trials to assess the potential therapeutic effects of HCQ in preeclampsia. Conducting clinical trials would offer a more comprehensive understanding of HCQ’s efficacy and safety, allowing us to explore its potential benefits and limitations in a real-world clinical setting. Full article

(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)

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14 pages, 4112 KiB

Open AccessArticle

Reduction in CgA-Derived CST Protein Level in HTR-8/SVneo and BeWo Trophoblastic Cell Lines Caused by the Preeclamptic Environment

by Michalina Bralewska, Tadeusz Pietrucha and Agata Sakowicz

Int. J. Mol. Sci. 2023, 24(8), 7124; https://doi.org/10.3390/ijms24087124 - 12 Apr 2023

Cited by 3 | Viewed by 1687

Abstract

One of the most dangerous complications of pregnancy is preeclampsia (PE), a disease associated with a high risk of maternal and fetal mortality and morbidity. Although its etiology remains unknown, the placenta is believed to be at the center of ongoing changes. One of the hormones produced by the placenta is chromogranin A (CgA). Thus far, its role in pregnancy and pregnancy-related disorders is enigmatic, yet it is known that both CgA and its derived peptide catestatin (CST) are involved in the majority of the processes that are disturbed in PE, such as blood pressure regulation or apoptosis. Therefore, in this study, the influence of the preeclamptic environment on the production of CgA using two cell lines, HTR-8/SVneo and BeWo, was investigated. Furthermore, the capacity of trophoblastic cells to secrete CST to the environment was tested, as well as the correlation between CST and apoptosis. This study provided the first evidence that CgA and CST proteins are produced by trophoblastic cell lines and that the PE environment has an impact on CST protein production. Furthermore, a strong negative correlation between CST protein level and apoptosis induction was found. Hence, both CgA and its derived peptide CST may play roles in the complex process of PE pathogenesis. Full article

(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)

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Review

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18 pages, 3722 KiB

Open AccessReview

Behind the Curtain of Abnormal Placentation in Pre-Eclampsia: From Molecular Mechanisms to Histological Hallmarks

by Anna Gusella, Guido Martignoni and Cinzia Giacometti

Int. J. Mol. Sci. 2024, 25(14), 7886; https://doi.org/10.3390/ijms25147886 - 18 Jul 2024

Viewed by 1459

Abstract

Successful human pregnancy needs several highly controlled steps to guarantee an oocyte’s fertilization, the embryo’s pre-implantation development, and its subsequent implantation into the uterine wall. The subsequent placenta development ensures adequate fetal nutrition and oxygenation, with the trophoblast being the first cell lineage to differentiate during this process. The placenta sustains the growth of the fetus by providing it with oxygen and nutrients and removing waste products. It is not surprising that issues with the early development of the placenta can lead to common pregnancy disorders, such as recurrent miscarriage, fetal growth restriction, pre-eclampsia, and stillbirth. Understanding the normal development of the human placenta is essential for recognizing and contextualizing any pathological aberrations that may occur. The effects of these issues may not become apparent until later in pregnancy, during the mid or advanced stages. This review discusses the process of the embryo implantation phase, the molecular mechanisms involved, and the abnormalities in those mechanisms that are thought to contribute to the development of pre-eclampsia. The review also covers the histological hallmarks of pre-eclampsia as found during the examination of placental tissue from pre-eclampsia patients. Full article

(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)

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19 pages, 1643 KiB

Open AccessReview

From Biomarkers to the Molecular Mechanism of Preeclampsia—A Comprehensive Literature Review

by Magda Rybak-Krzyszkowska, Jakub Staniczek, Adrianna Kondracka, Joanna Bogusławska, Sebastian Kwiatkowski, Tomasz Góra, Michał Strus and Wojciech Górczewski

Int. J. Mol. Sci. 2023, 24(17), 13252; https://doi.org/10.3390/ijms241713252 - 26 Aug 2023

Cited by 8 | Viewed by 2946

Abstract

Preeclampsia (PE) is a prevalent obstetric illness affecting pregnant women worldwide. This comprehensive literature review aims to examine the role of biomarkers and understand the molecular mechanisms underlying PE. The review encompasses studies on biomarkers for predicting, diagnosing, and monitoring PE, focusing on their molecular mechanisms in maternal blood or urine samples. Past research has advanced our understanding of PE pathogenesis, but the etiology remains unclear. Biomarkers such as PlGF, sFlt-1, PP-13, and PAPP-A have shown promise in risk classification and preventive measures, although challenges exist, including low detection rates and discrepancies in predicting different PE subtypes. Future perspectives highlight the importance of larger prospective studies to explore predictive biomarkers and their molecular mechanisms, improving screening efficacy and distinguishing between early-onset and late-onset PE. Biomarker assessments offer reliable and cost-effective screening methods for early detection, prognosis, and monitoring of PE. Early identification of high-risk women enables timely intervention, preventing adverse outcomes. Further research is needed to validate and optimize biomarker models for accurate prediction and diagnosis, ultimately improving maternal and fetal health outcomes. Full article

(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)

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19 pages, 775 KiB

Open AccessReview

Endogenous Digitalis-like Factors as a Key Molecule in the Pathophysiology of Pregnancy-Induced Hypertension and a Potential Therapeutic Target in Preeclampsia

by Maciej W. Socha, Jakub Chmielewski, Miłosz Pietrus and Mateusz Wartęga

Int. J. Mol. Sci. 2023, 24(16), 12743; https://doi.org/10.3390/ijms241612743 - 13 Aug 2023

Cited by 2 | Viewed by 2142

Abstract

Preeclampsia (PE), the most severe presentation of hypertensive disorders of pregnancy, is the major cause of morbidity and mortality linked to pregnancy, affecting both mother and fetus. Despite advances in prophylaxis and managing PE, delivery of the fetus remains the only causative treatment available. Focus on complex pathophysiology brought the potential for new treatment options, and more conservative options allowing reduction of feto-maternal complications and sequelae are being investigated. Endogenous digitalis-like factors, which have been linked to the pathogenesis of preeclampsia since the mid-1980s, have been shown to play a role in the pathogenesis of various cardiovascular diseases, including congestive heart failure and chronic renal disease. Elevated levels of EDLF have been described in pregnancy complicated by hypertensive disorders and are currently being investigated as a therapeutic target in the context of a possible breakthrough in managing preeclampsia. This review summarizes mechanisms implicating EDLFs in the pathogenesis of preeclampsia and evidence for their potential role in treating this doubly life-threatening disease. Full article

(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)

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30 pages, 1393 KiB

Open AccessReview

New Ideas for the Prevention and Treatment of Preeclampsia and Their Molecular Inspirations

by Agata Sakowicz, Michalina Bralewska, Magda Rybak-Krzyszkowska, Mariusz Grzesiak and Tadeusz Pietrucha

Int. J. Mol. Sci. 2023, 24(15), 12100; https://doi.org/10.3390/ijms241512100 - 28 Jul 2023

Cited by 9 | Viewed by 6043

Abstract

Preeclampsia (PE) is a pregnancy-specific disorder affecting 4–10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main symptoms generally appear after week 20 of gestation, scientific studies indicate that the mechanism underpinning PE is initiated at the beginning of gestation. It is known that the pathomechanism of preeclampsia is strongly related to inflammation and oxidative stress, which influence placentation and provoke endothelial dysfunction in the mother. However, as of yet, no “key players” regulating all these processes have been discovered. This might be why current therapeutic strategies intended for prevention or treatment are not fully effective, and the only effective method to stop the disease is the premature induction of delivery, mostly by caesarean section. Therefore, there is a need for further research into new pharmacological strategies for the treatment and prevention of preeclampsia. This review presents new preventive methods and therapies for PE not yet recommended by obstetrical and gynaecological societies. As many of these therapies are in preclinical studies or under evaluation in clinical trials, this paper reports the molecular targets of the tested agents or methods. Full article

(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)

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