RESUMO
After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.
Assuntos
Endométrio , Neovascularização Patológica , Fator de Crescimento Placentário , Pré-Eclâmpsia , Proteínas Serina-Treonina Quinases , Fatores de Transcrição , Feminino , Humanos , Gravidez , Endométrio/metabolismo , Endométrio/irrigação sanguínea , Ensaio de Imunoadsorção Enzimática , Proteínas Imediatamente Precoces/metabolismo , Neovascularização Patológica/metabolismo , Fator de Crescimento Placentário/metabolismo , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Fatores de Transcrição/metabolismoRESUMO
The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to the global COVID-19 pandemic, significantly impacting the health of pregnant women. Obstetric populations, already vulnerable, face increased morbidity and mortality related to COVID-19, aggravated by preexisting comorbidities. Recent studies have shed light on the potential correlation between COVID-19 and preeclampsia (PE), a leading cause of maternal and perinatal morbidity worldwide, emphasizing the significance of exploring the relationship between these two conditions. Here, we review the pathophysiological similarities that PE shares with COVID-19, with a particular focus on severe COVID-19 cases and in PE-like syndrome cases related with SARS-CoV-2 infection. We highlight cellular and molecular mechanistic inter-connectivity between these two conditions, for example, regulation of renin-angiotensin system, tight junction and barrier integrity, and the complement system. Finally, we discuss how COVID-19 pandemic dynamics, including the emergence of variants and vaccination efforts, has shaped the clinical scenario and influenced the severity and management of both COVID-19 and PE. Continued research on the mechanisms of SARS-CoV-2 infection during pregnancy and the potential risk of developing PE from previous infections is warranted to delineate the complexities of COVID-19 and PE interactions and to improve clinical management of both conditions.
Assuntos
COVID-19 , Pré-Eclâmpsia , Complicações Infecciosas na Gravidez , SARS-CoV-2 , Humanos , COVID-19/fisiopatologia , COVID-19/imunologia , Gravidez , Feminino , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/imunologia , SARS-CoV-2/fisiologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Sistema Renina-AngiotensinaRESUMO
Preeclampsia (PE) is a multifactorial pregnancy disorder characterized by hypertension and proteinuria, posing significant risks to both maternal and fetal health. Despite extensive research, its complex pathophysiology remains incompletely understood. This narrative review aims to elucidate the intricate mechanisms contributing to PE, focusing on abnormal placentation, maternal systemic response, oxidative stress, inflammation, and genetic and epigenetic factors. This review synthesizes findings from recent studies, clinical trials, and meta-analyses, highlighting key molecular and cellular pathways involved in PE. The review integrates data on oxidative stress biomarkers, angiogenic factors, immune interactions, and mitochondrial dysfunction. PE is initiated by poor placentation due to inadequate trophoblast invasion and improper spiral artery remodeling, leading to placental hypoxia. This triggers the release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), causing widespread endothelial dysfunction and systemic inflammation. Oxidative stress, mitochondrial abnormalities, and immune dysregulation further exacerbate the condition. Genetic and epigenetic modifications, including polymorphisms in the Fms-like tyrosine kinase 1 (FLT1) gene and altered microRNA (miRNA) expression, play critical roles. Emerging therapeutic strategies targeting oxidative stress, inflammation, angiogenesis, and specific molecular pathways like the heme oxygenase-1/carbon monoxide (HO-1/CO) and cystathionine gamma-lyase/hydrogen sulfide (CSE/H2S) pathways show promise in mitigating preeclampsia's effects. PE is a complex disorder with multifactorial origins involving abnormal placentation, endothelial dysfunction, systemic inflammation, and oxidative stress. Despite advances in understanding its pathophysiology, effective prevention and treatment strategies remain limited. Continued research is essential to develop targeted therapies that can improve outcomes for both mothers and their babies.
Assuntos
Estresse Oxidativo , Pré-Eclâmpsia , Humanos , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/metabolismo , Gravidez , Feminino , Epigênese Genética , Inflamação/metabolismo , Biomarcadores , Placenta/metabolismo , Placenta/fisiopatologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
To analyze the possible association between serum uric acid (SUA) and nocturnal hypertension and to evaluate the ability of these variables (alone or in combination) to predict preeclampsia (PE) we conducted a historical cohort study in 532 high-risk pregnancies. Women were divided according to SUA values and nocturnal blood pressure (BP) into four groups: 1- normal SUA and nocturnal normotension; 2- high SUA and nocturnal normotension; 3- normal SUA and nocturnal hypertension and 4- high SUA and nocturnal hypertension. High SUA was defined by the top quartile values and nocturnal hypertension as BP ≥ 120/70 mmHg, using ambulatory blood pressure monitoring (ABPM), during nocturnal rest. Risks for PE were compared using logistic regression. SUA had a weak but significant correlation with daytime systolic ABPM (r = 0.11, p = 0.014), daytime diastolic ABPM (r = 0.13, p = 0.004), nighttime systolic ABPM (r = 0.16, p < 0.001) and nighttime diastolic ABPM (r = 0.18, p < 0.001). Also, all ABPM values were higher in women with high SUA. The absolute risk of PE increased through groups: 6.5%, 13.1%, 31.2%, and 47.9% for groups 1, 2, 3, and 4, respectively, p < 0.001. Compared with Group 1, Group 3 (OR 6.29 95%CI 3.41-11.60), but not Group 2 (OR 2.15 95%CI 0.88-5.24), had statistically significant higher risk for PE. Group 4 (women with both, high SUA and nocturnal hypertension) had the highest risk (OR 13.11 95%CI 6.69-25.70). Risks remained statistically significant after the adjustment for relevant variables. In conclusion, the combination of SUA > 4 mg/dL and nocturnal BP > 120/70 mmHg implies a very high risk to developed PE.
Assuntos
Ritmo Circadiano , Pré-Eclâmpsia , Ácido Úrico , Humanos , Feminino , Ácido Úrico/sangue , Gravidez , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/epidemiologia , Adulto , Fatores de Risco , Monitorização Ambulatorial da Pressão Arterial , Pressão Sanguínea , Gravidez de Alto Risco/sangue , Biomarcadores/sangue , Hipertensão/sangue , Hipertensão/fisiopatologia , Hipertensão/diagnóstico , Adulto Jovem , Modelos Logísticos , Medição de RiscoRESUMO
INTRODUCTION: Citral is a low-toxicity monoterpene that has a vasodilator effect on various smooth muscles, and The present study aimed to evaluate its vasorelaxant effect on umbilical vessels of normotensive parturients (NTP) and with preeclampsia parturients (PEP). METHOD: Segments of human umbilical artery (HUA) and vein (HUV) of NTP or PEP were mounted in a bath to record the force of contraction, under tension of 3.0 gf and contracted with the contracting agents: K+ (60 mM), 5 -HT (10 µM) and Ba2+ (1-30 mM). Next, the effect of citral (1-3000 µM) on these contractions and on basal tone was evaluated. RESULTS: In HUA and HUV, citral (1-1000 µM), in NTP condition, inhibited contractions evoked by K+ (IC50 of 413.5 and 271.3, respectively) and by 5-HT (IC50 of 164.8 and 574.3). In the PEP condition, in HUA and HUV, citral also inhibited the contractions evoked by K+ (IC50 of 363.3 and 218.3, respectively) and 5-HT (IC50 of 432.1 and 520.4). At a concentration of 1000 µM, citral completely or almost completely (>90 %) inhibited all contractions. At a concentration of 100-1000 µM, citral, in general, was already able to reduce the contraction induced by 1-3 mM Ba2+ in both AUH and VUH, under NTP and PEP conditions. DISCUSSION: Citral has been shown to be an effective HUA and HUV vasodilator in NTP and PEP. As its toxicity is low, it suggests that this substance can be considered a potential therapeutic agent.
Assuntos
Monoterpenos Acíclicos , Monoterpenos , Pré-Eclâmpsia , Artérias Umbilicais , Vasodilatadores , Humanos , Feminino , Gravidez , Pré-Eclâmpsia/fisiopatologia , Monoterpenos Acíclicos/farmacologia , Monoterpenos/farmacologia , Artérias Umbilicais/efeitos dos fármacos , Adulto , Vasodilatadores/farmacologia , Veias Umbilicais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Objective: Potassium channels have an important role in the vascular adaptation during pregnancy and a reduction in the expression of adenosine triphosphate-sensitive potassium channels (Katp) has been linked to preeclampsia. Activation of Katp induces vasodilation; however, no previous study has been conducted to evaluate the effects of the inhibition of these channels in the contractility of preeclamptic arteries. Glibenclamide is an oral antihyperglycemic agent that inhibits Katp and has been widely used in vascular studies. Methods: To investigate the effects of the inhibition of Katp, umbilical arteries of preeclamptic women and women with healthy pregnancies were assessed by vascular contractility experiments, in the presence or absence of glibenclamide. The umbilical arteries were challenged with cumulative concentrations of potassium chloride (KCl) and serotonin. Results: There were no differences between the groups concerning the maternal age and gestational age of the patients. The percentage of smokers, caucasians and primiparae per group was also similar. On the other hand, blood pressure parameters were elevated in the preeclamptic group. In addition, the preeclamptic group presented a significantly higher body mass index. The newborns of both groups presented similar APGAR scores and weights. Conclusion: In the presence of glibenclamide, there was an increase in the KCl-induced contractions only in vessels from the PE group, showing a possible involvement of these channels in the disorder.
Assuntos
Glibureto , Pré-Eclâmpsia , Artérias Umbilicais , Humanos , Feminino , Gravidez , Pré-Eclâmpsia/fisiopatologia , Artérias Umbilicais/fisiopatologia , Adulto , Glibureto/farmacologia , Vasoconstrição/efeitos dos fármacos , Adulto Jovem , Canais KATP/metabolismo , Cloreto de Potássio/farmacologiaRESUMO
Oxidative stress and mitochondrial dysfunction are important elements for the pathophysiology of preeclampsia (PE), a multisystemic hypertensive syndrome of pregnancy, characterized by endothelial dysfunction and responsible for a large part of maternal and fetal morbidity and mortality worldwide. Researchers have dedicated their efforts to unraveling the intricate ways in which certain molecules influence both energy metabolism and oxidative stress. Exploring established methodologies from existing literature, shows that these investigations predominantly focus on the placenta, identified as a pivotal source that drives the changes observed in the disease. In this review, we discuss the role of oxidative stress in pathophysiology of PE, as well as metabolic/endothelial dysfunction. We further discuss the use of seahorse analyzers to study real-time bioenergetics of endothelial cells. Although the benefits are clear, few studies have presented results using this method to assess mitochondrial metabolism in these cells. We performed a search on MEDLINE/PubMed using the terms "Seahorse assay and endothelial dysfunction in HUVEC" as well as "Seahorse assay and preeclampsia". From our research, we selected 16 original peer-review papers for discussion. Notably, the first search retrieved studies involving Human Umbilical Vein Endothelial Cells (HUVECs) but none investigating bioenergetics in PE while the second search retrieved studies exploring the technique in PE but none of the studies used HUVECs. Additional studies are required to investigate real-time mitochondrial bioenergetics in PE. Clearly, there is a need for more complete studies to examine the nuances of mitochondrial bioenergetics, focusing on the contributions of HUVECs in the context of PE.
Assuntos
Metabolismo Energético , Células Endoteliais da Veia Umbilical Humana , Mitocôndrias , Estresse Oxidativo , Pré-Eclâmpsia , Humanos , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/patologia , Gravidez , Feminino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Animais , Valor Preditivo dos TestesRESUMO
OBJECTIVES: To describe the epidemiological and clinical profile of the patients with preeclampsia in a hospital in the Amazon region. STUDY DESIGN: Observational descriptive cross-sectional study, performed at Fundação Santa Casa de Misericórdia do Pará, a maternity hospital in Pará, Brazil. The pregnant patients admitted between July 1st and December 31st 2018 due to pre-eclampsia had their medical records researched to describe their epidemiological profile, medical history, obstetric profile and clinical manifestations of pre-eclampsia. Patients with incomplete data were not included in the missing variable's rate. MAIN OUTCOME MEASURES: 3450 pregnant patients were admitted, and 381 of them due to pre-eclampsia, revealing a 11.04% prevalence. RESULTS: Both arithmetic mean and median of maternal age were approximately 27 years. 94.25% of the participants were parda. Regarding medical history, 50.27% had chronic hypertension, and 37.23% had urinary tract infection during pregnancy. The obstetric profile revealed that 42.26% were primigravid, and 30% of the multigravid participants had already manifested pregnancy hypertension. 78.1% of the participants attended less than 6 prenatal consultations, and 10.03% used chemical substances during pregnancy. Twin pregnancy had a 3.14% prevalence. Beyond hypertension and proteinuria, scotoma was the most frequent (28.57%) clinical manifestation. 2.36% of the patients developed seizures, mostly (55.55%) before 37 weeks of pregnancy. CONCLUSIONS: The profile of the participants was mean age 27 years, parda race, with chronic hypertension, single fetus, multigravid without previous pregnancy hypertension, with less than 6 prenatal consultations, no use of chemical substances and without any manifestations of pre-eclampsia beyond hypertension and proteinuria.
Assuntos
Nível de Saúde , Pré-Eclâmpsia/epidemiologia , Adulto , Brasil/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Maternidades/estatística & dados numéricos , Humanos , Pré-Eclâmpsia/fisiopatologia , Gravidez , PrevalênciaRESUMO
BACKGROUND: Approximately 5-7 % of pregnant women have hypertension during pregnancy, requiring antihypertensive drug treatment. There have been a lack of studies evaluating how drug-related problems (DRPs) affect morbidity or mortality in the postpartum period among women with a history of preeclampsia. OBJECTIVE: To determine the influence of drug-related problems on length of hospital stay of postpartum women with a history of preeclampsia. METHODS: This cross-sectional study included postpartum women diagnosed with preeclampsia, from June to November 2016, in two teaching maternity hospitals in Brazil. The outcomes assessed were, length of hospital stay of postpartum women. The DRPs were classified through the Pharmaceutical Care Network Europe Foundation (PCNE) v 8.01. RESULTS: 600 women were included, and 354 (59%) were exposed to at least one DRP. The most frequent DRPs were no administration of the prescribed medication, lack of prescription of a medication, although the indication was clear, and ineffectiveness (unknown reason). In patients exposed to DRP, the average length of hospital stay after labour was 5.4 (S.D. 3.6) days versus 4.4 (S.D. 3.3) days in patients non-exposed to DRP (p = 0.0001). The period (in days) to achieve blood pressure control after labour was 4.5 (S.D. 3.5) 3.5 (S.D. 3.2), respectively (p = 0.0001). There were no deaths during the study. CONCLUSION AND RELEVANCE: Drug-related problems significantly increased the length of hospital stay in postpartum women with a history of preeclampsia.