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1.
Hipertens. riesgo vasc ; 37(2): 72-77, abr.-jun. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-189194

RESUMO

El sistema renina-angiotensina (SRA) es una cascada hormonal que regula presión arterial, electrólitos y balance hídrico. La angiotensinaII (AII) ejerce sus efectos a través de los receptores AT1 y AT2. El AT1 se encuentra en el sincitiotrofoblasto; el AT2 predomina durante el desarrollo fetal y su estimulación inhibe el crecimiento celular, aumenta la apoptosis, causa vasodilatación y regula el desarrollo del tejido fetal. Existe además un SRA en la placenta, y la generación local de AII es responsable de la activación de los receptores AT1 del trofoblasto. En el embarazo normal, concomitantemente con reducción de los niveles de presión arterial, se produce un aumento del SRA circulante, pero la presión arterial no sube porque existe refractariedad a la AII, cosa que no ocurre en la preeclampsia. Revisamos la función del SRA en el embarazo normal y en la preeclampsia


The renin-angiotensin system (ARS) is a hormonal cascade that regulates blood pressure, electrolytes and water balance. AngiotensinII (AII) exerts its effects through the AT1 and AT2 receptors. AT1 is found in the syncytiotrophoblast, AT2 predominates during foetal development and its stimulation inhibits cell growth, increases apoptosis, causes vasodilation and regulates the development of foetal tissue. There is also an SRA in the placenta. The local generation of AII is responsible for the activation of AT1 receptors in the trophoblast. In normal pregnancy, concomitantly with reduction of blood pressure the circulating RAS increases, but blood pressure does not rise due to AII refractoriness, which does not occur in preeclampsia. We review the role of the SRA in normal pregnancy and preeclampsia


Assuntos
Humanos , Feminino , Gravidez , Sistema Renina-Angiotensina/efeitos dos fármacos , Pré-Eclâmpsia/metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Hemodinâmica/efeitos dos fármacos , Albumina Sérica/efeitos dos fármacos , Índice de Gravidade de Doença , Espaço Extracelular/efeitos dos fármacos , Homeostase/efeitos dos fármacos
2.
BJOG ; 127(11): 1374-1380, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32479682

RESUMO

OBJECTIVES: To investigate the incidence of clinical, ultrasonographic and biochemical findings related to pre-eclampsia (PE) in pregnancies with COVID-19, and to assess their accuracy to differentiate between PE and the PE-like features associated with COVID-19. DESIGN: A prospective, observational study. SETTING: Tertiary referral hospital. PARTICIPANTS: Singleton pregnancies with COVID-19 at >20+0  weeks. METHODS: Forty-two consecutive pregnancies were recruited and classified into two groups: severe and non-severe COVID-19, according to the occurrence of severe pneumonia. Uterine artery pulsatility index (UtAPI) and angiogenic factors (soluble fms-like tyrosine kinase-1/placental growth factor [sFlt-1/PlGF]) were assessed in women with suspected PE. MAIN OUTCOME MEASURES: Incidence of signs and symptoms related to PE, such as hypertension, proteinuria, thrombocytopenia, elevated liver enzymes, abnormal UtAPI and increased sFlt-1/PlGF. RESULTS: Thirty-four cases were classified as non-severe and 8 as severe COVID-19. Five (11.9%) women presented signs and symptoms of PE, all five being among the severe COVID-19 cases (62.5%). However, abnormal sFlt-1/PlGF and UtAPI could only be demonstrated in one case. One case remained pregnant after recovery from severe pneumonia and had a spontaneous resolution of the PE-like syndrome. CONCLUSIONS: Pregnant women with severe COVID-19 can develop a PE-like syndrome that might be distinguished from actual PE by sFlt-1/PlGF, LDH and UtAPI assessment. Healthcare providers should be aware of its existence and monitor pregnancies with suspected pre-eclampsia with caution. TWEETABLE ABSTRACT: This study shows that a pre-eclampsia-like syndrome could be present in some pregnancies with severe COVID-19.


Assuntos
Infecções por Coronavirus/fisiopatologia , Síndrome HELLP/fisiopatologia , Fator de Crescimento Placentário/metabolismo , Pneumonia Viral/fisiopatologia , Pré-Eclâmpsia/fisiopatologia , Complicações Infecciosas na Gravidez/fisiopatologia , Artéria Uterina/diagnóstico por imagem , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Betacoronavirus , Pressão Sanguínea , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Feminino , Síndrome HELLP/etiologia , Síndrome HELLP/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Proteinúria/etiologia , Proteinúria/fisiopatologia , Fluxo Pulsátil , Índice de Gravidade de Doença , Centros de Atenção Terciária , Trombocitopenia/etiologia , Trombocitopenia/fisiopatologia
3.
Arch Biochem Biophys ; 688: 108366, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32387473

RESUMO

Preeclampsia (PE) is a pregnancy-related syndrome and has become the leading cause of maternal and neonatal morbidity and mortality. LncRNA has been elucidated to play critical roles in the phenotype of trophoblast cells. However, the effect of AK002210 has not been reported. We aim to investigate the effect of AK002210 on the phenotype of trophoblast cells. Quantitative reverse transcription PCR was used to assess the gene expression. CCK-8 assay was used to evaluate the cell proliferation. Transwell assay was performed to detect the migration and invasion of trophoblast cells. Luciferase assay and rescue experiment were carried out to verify the interaction between miR-590-3p and AK002210 as well as NLR family apoptosis inhibitory protein (NAIP). The results revealed that AK002210 promoted the proliferation, migration and invasion of trophoblast cell while AK002210 knockdown inhibited that. Mechanically, we found that AK002210 was targeted by miR-590-3p. Moreover, miR-590-3p also directly targets NAIP which served as a ceRNA of AK002210. Rescue experiment showed that miR-590-3p reversed the effect of AK002210 which further confirmed their interaction. Moreover, AK002210 was proved to participated in the regulation of ERK/MMP-2 signal axis. In conclusion, we found that AK002210 knockdown may play a critical role in the progression of PE via miR-590-3p/NAIP and ERK/MMP signaling. It has potential to be a novel prognostic or therapeutic marker of PE.


Assuntos
Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Pré-Eclâmpsia/fisiopatologia , RNA Longo não Codificante/fisiologia , Transdução de Sinais/fisiologia , Trofoblastos/fisiologia , Apoptose/fisiologia , Linhagem Celular , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Metaloproteinase 2 da Matriz/metabolismo , MicroRNAs/metabolismo , Proteína Inibidora de Apoptose Neuronal/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Gravidez , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
4.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R26-R32, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432917

RESUMO

Preeclampsia is a pregnancy-specific disorder that impacts 5-8% of pregnancies and has long-term cardiovascular and metabolic implications for both mother and fetus. The mechanisms are unclear; however, it is believed that preeclampsia is characterized by abnormal vascularization during placentation resulting in the manifestation of clinical signs such as hypertension, proteinuria, and endothelial dysfunction. Although there is no current cure to alleviate the clinical signs, an emerging area of interest in the field is the influence of environmental factors including diet on the risk of preeclampsia. Because preeclampsia has serious cardiovascular implications to both the mother and fetus and most antihypertensive medications are contraindicated in pregnancy, it is important to investigate other potential therapeutic options such as dietary manipulation. The emerging field of nutrigenomics links diet with the gene expression of known pathways such as oxidative stress and inflammation via microbiome-mediated metabolites and could serve as one potential avenue of therapeutic targets for preeclampsia. Although the exact role of nutrition in the pathogenesis of preeclampsia is unknown, this review will focus on known pathways involved in the development of preeclampsia and how dietary intake modulates the microbiome, oxidative stress, and inflammation with an emphasis on nutrigenomics as a potential avenue of further investigation to better understand this pathology.


Assuntos
Meio Ambiente , Pré-Eclâmpsia/metabolismo , Adulto , Dieta , Feminino , Humanos , Microbiota , Nutrigenômica , Pré-Eclâmpsia/genética , Gravidez
5.
Am J Physiol Regul Integr Comp Physiol ; 318(6): R1047-R1057, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32374620

RESUMO

Preeclampsia is a spontaneously occurring, pregnancy-specific syndrome that is clinically diagnosed by new onset hypertension and proteinuria. Epidemiological evidence describes an association between a history of preeclampsia and increased risk for cardiovascular disease in later life; however, the mechanism(s) driving this relationship are unclear. Our study aims to leverage a novel preeclampsia-like mouse model, the C1q-/- model, to help elucidate the acute and persistent vascular changes during and following a preeclampsia-like pregnancy. Female C57BL/6J mice were mated to C1q-/- male mice to model a preeclampsia-like pregnancy ("PE-like"), and the maternal cardiovascular phenotype (blood pressure, renal function, systemic glycocalyx, and ex vivo vascular function) was assessed in late pregnancy and postpartum at 6 and 10 mo of age. Uncomplicated, normotensive pregnancies (female C57BL/6J bred to male C57BL/6J mice) served as age-matched controls. In pregnancy, PE-like dams exhibited increased systolic and diastolic pressure during mid- and late gestation, renal dysfunction, fetal growth restriction, and reduced placental efficiency. Ex vivo wire myography studies of mesenteric arteries revealed severe pregnancy-specific endothelial-dependent and -independent vascular dysfunction. At 3 and 7 mo postpartum (6 and 10 mo old, respectively), hypertension resolved in PE-like dams, whereas mild vascular dysfunction persisted at 3 mo postpartum. In conclusion, the female C57BL/6J-by-male C57BL/6J C1q-/- model recapitulates many aspects of the human preeclampsia syndrome in a low-risk, wild-type female mouse. The pregnancy-specific phenotype results in systemic maternal endothelial-dependent and -independent vascular dysfunction that persists postpartum.


Assuntos
Complemento C1q/metabolismo , Pré-Eclâmpsia/metabolismo , Animais , Pressão Sanguínea/fisiologia , Complemento C1q/genética , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Knockout , Placenta/irrigação sanguínea , Pré-Eclâmpsia/genética , Gravidez
6.
PLoS One ; 15(4): e0232287, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32339208

RESUMO

OBJECTIVE: Sleep-disordered breathing (SDB) is characterised by intermittent hypoxemia, sympathetic activation and widespread endothelial dysfunction, sharing pathophysiologic features with the hypertensive disorders of pregnancy. We sought to determine whether coexisting SDB would adversely impact the outcomes of women with gestational hypertension (GH) and preeclampsia (PE), and healthy matched controls. STUDY DESIGN: Women diagnosed with GH or PE along with BMI- and gestation-matched normotensive controls underwent polysomnography in late pregnancy to establish the presence or absence of SDB (RDI ≥ 5). Clinical outcomes of hypertensive disease severity were compared between groups, and venous blood samples were taken in the third trimester and at delivery to examine for any impact of SDB on the anti-angiogenic markers of PE. RESULTS: Data was available for 17 women with PE, 24 women with GH and 44 controls. SDB was diagnosed in 41% of the PE group, 63% of the GH group and 39% of the control group. Women with PE and co-existing SDB did not have worse outcomes in terms of gestation at diagnosis of PE (SDB = 29.1 (25.9, 32.1) weeks vs. no SDB = 32.0 (29.0, 33.9), p = n.s.) and days between diagnosis of PE and delivery (SDB = 20.0 (4.0, 35.0) days vs. no SDB = 10.5 (9.0, 14.0), p = n.s.). There were also no differences in severity of hypertension, antihypertensive treatment and biochemical, haematological and anti-angiogenic markers of PE between SDB and no SDB groups. Similar results were observed among women with GH. Healthy control women with SDB were no more likely to develop a hypertensive disorder of pregnancy in the later stages of pregnancy (SDB = 5.9% vs. no SDB = 7.4%, p = n.s.). Increasing the threshold for diagnosis of SDB to RDI ≥ 15 did not unmask a worse prognosis. CONCLUSION: The presence of SDB during pregnancy did not worsen the disease course of GH or PE, and was not associated with high blood pressure or anti-angiogenic markers of hypertensive disease amongst healthy pregnant women. Given the numerous reports of the relationship between SDB and diagnosis of hypertensive disorders of pregnancy, it appears more work is required to distinguish causal, versus confounding, pathways.


Assuntos
Hipertensão Induzida pela Gravidez/etiologia , Hipertensão Induzida pela Gravidez/fisiopatologia , Síndromes da Apneia do Sono/complicações , Síndromes da Apneia do Sono/fisiopatologia , Adulto , Anti-Hipertensivos/uso terapêutico , Feminino , Humanos , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Hipertensão Induzida pela Gravidez/metabolismo , Fator de Crescimento Placentário/metabolismo , Polissonografia/métodos , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Fatores de Risco , Síndromes da Apneia do Sono/metabolismo
7.
Clin Sci (Lond) ; 134(8): 1001-1025, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32337535

RESUMO

Placental microRNAs (miRNAs) regulate the placental transcriptome and play a pathological role in preeclampsia (PE), a hypertensive disorder of pregnancy. Three PE rodent model studies explored the role of placental miRNAs, miR-210, miR-126, and miR-148/152 respectively, by examining expression of the miRNAs, their inducers, and potential gene targets. This review evaluates the role of miR-210, miR-126, and miR-148/152 in PE by comparing findings from the three rodent model studies with in vitro studies, other animal models, and preeclamptic patients to provide comprehensive insight into genetic components and pathological processes in the placenta contributing to PE. The majority of studies demonstrate miR-210 is upregulated in PE in part driven by HIF-1α and NF-κBp50, stimulated by hypoxia and/or immune-mediated processes. Elevated miR-210 may contribute to PE via inhibiting anti-inflammatory Th2-cytokines. Studies report an up- and downregulation of miR-126, arguably reflecting differences in expression between cell types and its multifunctional capacity. MiR-126 may play a pro-angiogenic role by mediating the PI3K-Akt pathway. Most studies report miR-148/152 family members are upregulated in PE. Evidence suggests they may inhibit DNA methylation of genes involved in metabolic and inflammatory pathways. Given the genetic heterogeneity of PE, it is unlikely that a single placental miRNA is a suitable therapeutic target for all patients. Investigating miRNAs in PE subtypes in patients and animal models may represent a more appropriate approach going forward. Developing methods for targeting placental miRNAs and specific placental cell types remains crucial for research seeking to target placental miRNAs as a novel treatment for PE.


Assuntos
MicroRNAs/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , MicroRNAs/genética , Pré-Eclâmpsia/genética , Gravidez
8.
Pregnancy Hypertens ; 20: 131-136, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32299060

RESUMO

OBJECTIVES: Preeclampsia is a cardiovascular pregnancy complication that occurs in 5-10% of pregnancies and it can lead to a number of pregnancy complications including maternal and foetal death. Long-term, preeclampsia is associated with up to 8-fold increased risk of cardiovascular disease (CVD) for both mothers and their offspring. The lack of mechanistic data in relation to the causes or consequences of preeclampsia has prevented the development of effective therapeutic and monitoring strategies. STUDY DESIGN: This study investigates common underlying mechanisms of preeclampsia and CVD, specifically hypertension and heart failure with preserved ejection fraction (HFpEF), using "in silico" approach of publicly available datasets. Integrated techniques were designed to mine data repositories and identify relevant biomarkers associated with these three conditions. MAIN OUTCOMES MEASURES: The knowledge base tools were employed that enabled the analysis of these biomarkers to discover potential molecular and biological links between these three conditions. RESULTS: Our bioinformatics "in silico" analyses of the publically available datasets identified 76 common biomarkers between preeclampsia, hypertension and HFpEF. These biomarkers were representative of 29 pathways commonly enriched across the three conditions which were largely related to inflammation, metabolism, angiogenesis, remodelling, haemostasis, apoptosis and the renin-angiotensin-aldosterone (RAAS) system. CONCLUSIONS: This bioinformatics approach uses the wealth of scientific data available in public repositories to gain a deeper understanding of the overlapping pathogenic mechanisms of associated diseases, which could be explored as biomarkers or targets to prevent long-term cardiovascular complications such as hypertension and HFpEF following preeclampsia.


Assuntos
Redes Reguladoras de Genes , Insuficiência Cardíaca/genética , Hipertensão/genética , Pré-Eclâmpsia/genética , Transdução de Sinais/genética , Pressão Sanguínea , Biologia Computacional , Bases de Dados Genéticas , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Volume Sistólico , Função Ventricular Esquerda
9.
Life Sci ; 253: 117668, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32320706

RESUMO

AIMS: Preeclampsia (PE) accounts for the foremost cause of maternal and fetal mortality worldwide, whereas, there are no effective treatments for the disease yet. Long non-coding RNAs (lncRNAs) play critical roles in various human disorders, including PE. Here, we identified an up-regulated lncRNA HOTAIR, and explored its underlying mechanisms in PE. MAIN METHODS: qRT-PCR analysis was used to examine HOTAIR expression in PE tissues and cell lines. Trophoblast proliferation was examined by colony formation and 5-Ethynyl-2'-deoxyuridine (EdU) incorporation assays. Trophoblast migration and invasion was determined by transwell and wound healing assays. Bioinformatics analysis was performed to verify the regulation HOTAIR on miRNAs. The interaction between HOTAIR and EZH2 was detected using RNA immunoprecipitation assay (RIP). Chromatin immunoprecipitation (CHIP) assay was also performed to verify that the negative regulation of HOTAIR on miR-106a was dependent on the epigenetic repressor EZH2. KEY FINDINGS: HOTAIR was up-regulated in PE placenta tissues, which repressed the proliferation, migration and invasion of trophoblast cells. HOTAIR significantly repressed miR-106a expression and the reduced miR-106a level was also observed in placentas from PE patients. Additionally, miR-106a mimic enhanced the migration and invasion of trophoblast cells. Further mechanistic analyses implied that the action of HOTAIR is moderately attributable to its repression of miR-106a via association with EZH2. SIGNIFICANCE: High level of HOTAIR repressed the proliferation, migration and invasion of trophoblast cells through targeting miR-106 in an EZH2-dependent manner, which may provide new insights into the roles of HOTAIR and miR-106a as potential regulators in PE.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , MicroRNAs/metabolismo , Pré-Eclâmpsia/metabolismo , RNA Longo não Codificante/metabolismo , Sequência de Bases , Linhagem Celular , Proliferação de Células , Progressão da Doença , Repressão Epigenética , Feminino , Humanos , Placenta/metabolismo , Gravidez , Trofoblastos/citologia , Regulação para Cima
10.
PLoS One ; 15(3): e0230977, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32231385

RESUMO

INTRODUCTION: Pre-eclampsia is a major cause of maternal and fetal mortality and morbidity worldwide. Its pathophysiology remains unclear, but mitochondrial dysfunction and oxidative stress have been implicated. L-Ergothioneine is a naturally occurring, water-soluble betaine, that has demonstrated antioxidant properties. Using the reduced uterine perfusion pressure (RUPP) rat model of pre-eclampsia, this study aimed to define the plasma metabolic profile following treatment with L-Ergothioneine. METHODS: The effect of L-Ergothioneine (ET) treatment was explored using in vivo treatment in rats: Sham control (SC, n = 5), RUPP control (RC, n = 5), Sham +ET (ST, n = 5), RUPP +ET (RT, n = 5). Differential expression of plasma metabolites were obtained using untargeted liquid chromatography coupled to mass spectrometry. Statistical analysis was performed on normalised data comparing RC to SC, RT to RC, and RT to ST. Metabolites significantly altered (FDR < 0.05) were identified through database search. RESULTS: We report significantly lower levels of L-palmitoylcarnitine in RC compared to SC, a fatty acyl substrate involved in beta-oxidation in the mitochondria. We report that a metabolite that has been associated with oxidative stress (Glutamylcysteine) was detected at significantly higher levels in RT vs RC and RT vs ST. Five metabolites associated with inflammation were significantly lower in RT vs RC and three metabolites in RT vs ST, demonstrating the anti-inflammatory effects of ET in the RUPP rat model of pre-eclampsia. CONCLUSIONS: L-Ergothioneine may help preserve mitochondrial function by increasing antioxidant levels, and reducing inflammatory responses associated with pre-eclampsia. This study shows the potential of L-Ergothioneine as a treatment for pre-eclampsia.


Assuntos
Ergotioneína/farmacologia , Metaboloma/efeitos dos fármacos , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Perfusão , Gravidez , Pressão , Ratos , Ratos Sprague-Dawley
11.
PLoS One ; 15(4): e0230955, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315307

RESUMO

INTRODUCTION: Prediction models for gestational hypertension and preeclampsia have been developed with data and assumptions from developed countries. Their suitability and application for low resource settings have not been tested. This review aimed to identify and assess the methodological quality of prediction models for gestational hypertension and pre-eclampsia with reference to their application in low resource settings. METHODS: Using combinations of keywords for gestational hypertension, preeclampsia and prediction models seven databases were searched to identify prediction models developed with maternal data obtained before 20 weeks of pregnancy and including at least three predictors (Prospero registration CRD 42017078786). Prediction model characteristics and performance measures were extracted using the CHARMS, STROBE and TRIPOD checklists. The National Institute of Health quality assessment tools for observational cohort and cross-sectional studies were used for study quality appraisal. RESULTS: We retrieved 8,309 articles out of which 40 articles were eligible for review. Seventy-seven percent of all the prediction models combined biomarkers with maternal clinical characteristics. Biomarkers used as predictors in most models were pregnancy associated plasma protein-A (PAPP-A) and placental growth factor (PlGF). Only five studies were conducted in a low-and middle income country. CONCLUSIONS: Most of the studies evaluated did not completely follow the CHARMS, TRIPOD and STROBE guidelines in prediction model development and reporting. Adherence to these guidelines will improve prediction modelling studies and subsequent application of prediction models in clinical practice. Prediction models using maternal characteristics, with good discrimination and calibration, should be externally validated for use in low and middle income countries where biomarker assays are not routinely available.


Assuntos
Hipertensão Induzida pela Gravidez/etiologia , Pré-Eclâmpsia/etiologia , Biomarcadores/sangue , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Hipertensão Induzida pela Gravidez/sangue , Hipertensão Induzida pela Gravidez/metabolismo , Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/metabolismo , Gravidez , Proteína Plasmática A Associada à Gravidez/metabolismo
12.
Res Vet Sci ; 130: 73-78, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32146378

RESUMO

Pregnancy toxemia (PT) is considered one of the most common metabolic diseases with high impact on the production of small ruminants. The objective of this study was investigate possible myocardial damage in goats affected with PT by the determination of serum myocardial biomarkers CK-MB and cTnI. A total of 44 goats affected with PT, and 10 apparently healthy goats (control group or CG) were used in the study. In goats with PT, the serum concentrations of cTnI (0.43 ng/mL) were significantly higher than that in CG goats (0.06 ng/mL). Although CK-MB showed no significant difference, it was approximately three times higher in animals with PT. The serum concentrations of insulin were significantly lower in PT goats (5.03 ppmol/L) compared to CG goats (10.66 pmol/L). The serum concentrations of cortisol in PT goats (155.41 nmol/L) were significantly higher than that in CG goats (36.58 nmol/L). Results of this study indicate that a clinically significant myocardial damage might occur in goats affected with PT leading to significant elevations in values of cTnI and CK-MB. Therefore, these parameters could be used as a potential prognostic indicator in goats affected with this important disease.


Assuntos
Biomarcadores/metabolismo , Doenças das Cabras/metabolismo , Miocárdio/metabolismo , Pré-Eclâmpsia/veterinária , Animais , Feminino , Cabras , Pré-Eclâmpsia/metabolismo , Gravidez , Toxemia/metabolismo , Toxemia/veterinária
13.
Clin Sci (Lond) ; 134(6): 593-607, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32129439

RESUMO

Small extracellular vesicles (sEVs) released from the extravillous trophoblast (EVT) are known to regulate uterine spiral artery remodeling during early pregnancy. The bioactivity and release of these sEVs differ under differing oxygen tensions and in aberrant pregnancy conditions. Whether the placental cell-derived sEVs released from the hypoxic placenta contribute to the pathophysiology of preeclampsia is not known. We hypothesize that, in response to low oxygen tension, the EVT packages a specific set of proteins in sEVs and that these released sEVs interact with endothelial cells to induce inflammation and increase maternal systemic blood pressure. Using a quantitative MS/MS approach, we identified 507 differentially abundant proteins within sEVs isolated from HTR-8/SVneo cells (a commonly used EVT model) cultured at 1% (hypoxia) compared with 8% (normoxia) oxygen. Among these differentially abundant proteins, 206 were up-regulated and 301 were down-regulated (P < 0.05), and they were mainly implicated in inflammation-related pathways. In vitro incubation of hypoxic sEVs with endothelial cells, significantly increased (P < 0.05) the release of GM-CSF, IL-6, IL-8, and VEGF, when compared with control (i.e. cells without sEVs) and normoxic sEVs. In vivo injection of hypoxic sEVs into pregnant rats significantly increased (P < 0.05) mean arterial pressure with increases in systolic and diastolic blood pressures. We propose that oxygen tension regulates the release and bioactivity of sEVs from EVT and that these sEVs regulate inflammation and maternal systemic blood pressure. This novel oxygen-responsive, sEVs signaling pathway, therefore, may contribute to the physiopathology of preeclampsia.


Assuntos
Citocinas/metabolismo , Vesículas Extracelulares/química , Hipóxia/fisiopatologia , Oxigênio/metabolismo , Pré-Eclâmpsia/fisiopatologia , Animais , Pressão Arterial , Pressão Sanguínea , Citocinas/genética , Células Endoteliais/química , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Oxigênio/análise , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Trofoblastos/química , Trofoblastos/metabolismo
14.
Pregnancy Hypertens ; 20: 69-74, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32193148

RESUMO

OBJECTIVES: To immuno-localize histone H2A expression as a marker of neutrophil extracellular traps (NETs) in the placenta; and to quantify and compare the percentage H2A immune-expression as a marker of NETs in the placental intervillous space according to: pregnancy type, HIV status and across the study population. STUDY DESIGN: The participants to the study were a pregnant South African population group of African ancestry (n = 60) stratified as normotensive (N) (n = 30) or pre-eclamptic (PE) (n = 30) and further subdivided as HIV infected (HIV+) (n = 15) or HIV naïve (HIV-) (n = 15). Following informed consent placental tissue samples were obtained at the time of delivery. Immunohistochemistry using the anti-histone 2A (H2A) antibody as a biomarker of NETs, and morphometric image analysis was used to immuno-localize and quantify placental H2A immuno-expression respectively in the placental inter-villous space. Statistical analysis was performed using Graph Pad Prism software (Version 5). MAIN OUTCOME MEASURES: To determine if HIV neutralizes the elevated NETs in PE. RESULTS: NETs were localized within the inter-villous space surrounding the exchange villi and conducting villi of placental tissue. Based on HIV status, a significant elevation in H2A immuno-expression was observed in the HIV+ compared to the HIV- group (p = 0.0008) and in the pre-eclampsia HIV- compared to the normotensive HIV- group (p = 0.0008). However, a significant decline in H2A immuno-expression was observed in the PEHIV+ group compared to the NHIV+ group (p = 0.0072). CONCLUSIONS: Both PE and HIV elevate placental NETs; however, they synergistically downregulate NETs expression. Further investigations are required to interrogate the signaling pathways involved to establish potential NET-targeted therapeutic actions.


Assuntos
Armadilhas Extracelulares/química , Infecções por HIV/metabolismo , Placenta/química , Pré-Eclâmpsia/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Adolescente , Adulto , Biomarcadores/análise , Vilosidades Coriônicas/química , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/fisiopatologia , Histonas/análise , Humanos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/fisiopatologia , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/fisiopatologia , África do Sul , Adulto Jovem
15.
Pregnancy Hypertens ; 20: 83-91, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32199147

RESUMO

OBJECTIVES: There is avid interest in pravastatin as a therapeutic intervention for pre-eclampsia, however little is known on statin action on endothelial dysfunction. This study aimed to evaluate the ability of pravastatin, simvastatin and rosuvastatin to reduce pre-eclampsia-associated markers of endothelial dysfunction in human endothelial cells. STUDY DESIGN: Primary human umbilical vein endothelial cells (HUVECs) and uterine microvascular cells (UtMVs) were isolated and treated with 0.2, 2, 20 and 200 µM pravastatin, simvastatin and rosuvastatin for 24 h, either with or without pre-treatment with TNF-α to induce endothelial dysfunction. MAIN OUTCOME MEASURES: Cell viability (MTS) assays were performed and cells were visually inspected. Expression of endothelial dysfunction markers, endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM-1) were assessed by qPCR (n=3). Intracellular VCAM-1 protein was examined by Western Blotting (n=5). ET-1 and soluble fms-like tyrosine kinase-1 (sFLT-1) protein secretion was assessed by ELISA in HUVEC conditioned media (n=3). RESULTS: High doses of simvastatin and rosuvastatin significantly compromised HUVEC survival. 200 µM simvastatin significantly reduced UtMV survival. Abnormal cell structure was observed with these doses and thus were excluded from further analysis. The statins did not mitigate TNF-α induced ET-1 or VCAM-1 expression in either HUVECs or UtMVs, nor VCAM-1 protein expression in HUVECs. 0.2 µM pravastatin and simvastatin significantly reduced ET-1 and sFLT-1 protein secretion. CONCLUSIONS: Pravastatin significantly reduced secretion of both ET-1 and sFLT-1, key mediators of endothelial dysfunction. Importantly, pravastatin had no toxic effects, in contrast to rosuvastatin and simvastatin. This further supports selection of pravastatin for clinical applications to combat pre-eclampsia.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Pravastatina/farmacologia , Pré-Eclâmpsia/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Endotelina-1/genética , Endotelina-1/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Pravastatina/toxicidade , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Rosuvastatina Cálcica/farmacologia , Sinvastatina/farmacologia , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
16.
Orv Hetil ; 161(10): 389-395, 2020 Mar.
Artigo em Húngaro | MEDLINE | ID: mdl-32115993

RESUMO

Introduction: The treatment of preeclampsia, which occurs in 3-8% of pregnancies, is not yet resolved. In preeclampsia, NO synthesis is insufficient, which can contribute to hypertension, proteinuria and abnormal vascularization of the placenta. Decreased NO synthesis in the preeclamptic placenta may also be due to a decrease in the affinity of NO synthase for tetrahydrobiopterin (BH4), resulting in BH4 resistance. In recent years, pravastatin has been shown to prevent preeclampsia in animal models and in human studies. One of the known pleiotropic effects of pravastatin is that it increases NO synthase activity. Aim: Description of the effect of pravastatin on BH4-resistant NO synthase activity in the preeclamptic placenta. Method: NO synthase activity in the placental microsome was measured with C14 arginine substrate using healthy (n = 9) and preeclamptic (n = 9) samples. NO synthase activity was measured at 0.02 µM, physiological at 0.20 µM and pharmacological at 50 µM BH4. Results: One of the 9 preeclamptic patients was BH4-resistant; physiologic BH4 concentration did not significantly increase NO synthase activity, whereas healthy placental microsomes showed a mean increase of 60% (p<0.01), and BH4-sensitive preeclamptic specimen showed a 67% (p<0.01) increase. 10 µM pravastatin increased NO synthase activity by 32-38% at each BH4 concentration in healthy, BH4-sensitive and BH4-resistant preeclampsia samples. Conclusion: 10 µM pravastatin increased BH4-resistant placental NO synthase activity to a similar extent as placental physiological BH4 concentration (0.06-0.20 µM) to BH4-sensitive NO synthase activity. The NO synthase activity of BH4-resistant preeclamptic placenta can be increased by pravastatin to physiological level. Orv Hetil. 2020; 161(10): 389-395.


Assuntos
Biopterina/análogos & derivados , Óxido Nítrico Sintase/efeitos dos fármacos , Placenta/metabolismo , Pravastatina/farmacologia , Pré-Eclâmpsia/metabolismo , Feminino , Humanos , Gravidez
17.
Acta Obstet Gynecol Scand ; 99(8): 994-1002, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32017014

RESUMO

INTRODUCTION: Preeclampsia affects about 3% of singleton pregnancies and is characterized by placental dysfunction. It is associated with significant maternal and perinatal morbidity and mortality. The diagnosis of preeclampsia remains a challenge, and the clinical course can develop for weeks before a diagnosis is confirmed. National guidelines have approved placental growth factor (PlGF) testing to rule out suspected preeclampsia, but the utility of repeated PlGF measurement is unknown. The aim of this case series analysis was to evaluate the test performance of repeated PlGF sampling in women presenting with suspected preeclampsia, and to describe relevant clinical outcomes. MATERIAL AND METHODS: Women who presented to maternity services with suspected preeclampsia between 20+0 and 36+6  weeks' gestation who underwent repeat PlGF sampling with a minimum test interval of 7 days were assessed. The outcomes were delivery for preeclampsia within 14 days of sampling, the proportion changing PlGF categories, and time to delivery. RESULTS: In total, 289 women with suspected preeclampsia undergoing repeat PlGF sampling were included. PlGF <100 pg/mL had a high sensitivity (87.5%, 95% confidence interval [CI] 67.6%-97.3%) and a negative predictive value (97.7%, 95% CI 93.5%-99.5%) at the initial test (receiver operating characteristic [ROC] area 0.79, 95% CI 0.68-0.89). Similar test performance was seen for PlGF <100 pg/mL when undertaken as a repeat test (sensitivity 90.7%, 95% CI 85.2%-95.9%, negative predictive value 92.2%, 95% CI 85.3-96.6%). Overall, 25.6% of women changed PlGF category between the first and second PlGF tests. For each PlGF category, determination of time to delivery was similar for first and second tests. CONCLUSIONS: Repeat PlGF measurement demonstrates high negative predictive value for determining preeclampsia requiring delivery in 14 days. Repeat testing may be clinically useful to risk stratify women with ongoing symptoms of disease. Confirmation of the impact of these findings is required in further studies.


Assuntos
Fator de Crescimento Placentário/metabolismo , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/metabolismo , Adulto , Biomarcadores/metabolismo , Feminino , Humanos , Valor Preditivo dos Testes , Gravidez , Resultado da Gravidez , Medição de Risco , Sensibilidade e Especificidade
18.
Artigo em Inglês | MEDLINE | ID: mdl-32056469

RESUMO

Pregnancy and early life create specific psychosomatic challenges for the mother and child, such as changes in hemodynamics, resetting of the water-electrolyte balance, hypoxia, pain, and stress, that all play an important role in the regulation of the release of oxytocin and vasopressin. Both of these hormones regulate the water-electrolyte balance and cardiovascular functions, maturation of the cardiovascular system, and cardiovascular responses to stress. These aspects may be of particular importance in a state of emergency, such as hypertension in the mother or severe heart failure in the child. In this review, we draw attention to a broad spectrum of actions exerted by oxytocin and vasopressin in the pregnant mother and the offspring during early life. To this end, we discuss the following topics: 1) regulation of the secretion of oxytocin and vasopressin and expression of their receptors in the pregnant mother and child, 2) direct and indirect effects of oxytocin and vasopressin on the cardiovascular system in the healthy mother and fetus, and 3) positive and negative consequences of altered secretion of oxytocin and vasopressin in the mother with cardiovascular pathology and in the progeny with heart failure. The present survey provides evidence that moderate stimulation of the oxytocin and vasopressin receptors plays a beneficial role in the healthy pregnant mother and fetus; however, under pathophysiological conditions the inappropriate action of these hormones exerts several negative effects on the cardiovascular system of the mother and progeny and may potentially contribute to the pathophysiology of heart failure in early life.


Assuntos
Insuficiência Cardíaca/metabolismo , Ocitocina/metabolismo , Complicações Cardiovasculares na Gravidez/metabolismo , Vasopressinas/metabolismo , Animais , Feminino , Humanos , Recém-Nascido , Pré-Eclâmpsia/metabolismo , Gravidez , Equilíbrio Hidroeletrolítico
19.
Am J Clin Nutr ; 111(6): 1235-1243, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32108865

RESUMO

BACKGROUND: Conventional analytic approaches for studying diet patterns assume no dietary synergy, which can lead to bias if incorrectly modeled. Machine learning algorithms can overcome these limitations. OBJECTIVES: We estimated associations between fruit and vegetable intake relative to total energy intake and adverse pregnancy outcomes using targeted maximum likelihood estimation (TMLE) paired with the ensemble machine learning algorithm Super Learner, and compared these with results generated from multivariable logistic regression. METHODS: We used data from 7572 women in the Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be. Usual daily periconceptional intake of total fruits and total vegetables was estimated from an FFQ. We calculated the marginal risk of preterm birth, small-for-gestational-age (SGA) birth, gestational diabetes, and pre-eclampsia according to density of fruits and vegetables (cups/1000 kcal) ≥80th percentile compared with <80th percentile using multivariable logistic regression and Super Learner with TMLE. Models were adjusted for confounders, including other Healthy Eating Index-2010 components. RESULTS: Using logistic regression, higher fruit and high vegetable densities were associated with 1.1% and 1.4% reductions in pre-eclampsia risk compared with lower densities, respectively. They were not associated with the 3 other outcomes. Using Super Learner with TMLE, high fruit and vegetable densities were associated with fewer cases of preterm birth (-4.0; 95% CI: -4.9, -3.0 and -3.7; 95% CI: -5.0, -2.3), SGA (-1.7; 95% CI: -2.9, -0.51 and -3.8; 95% CI: -5.0, -2.5), and pre-eclampsia (-3.2; 95% CI: -4.2, -2.2 and -4.0; 95% CI: -5.2, -2.7) per 100 births, respectively, and high vegetable densities were associated with a 0.9% increase in risk of gestational diabetes. CONCLUSIONS: The differences in results between Super Learner with TMLE and logistic regression suggest that dietary synergy, which is accounted for in machine learning, may play a role in pregnancy outcomes. This innovative methodology for analyzing dietary data has the potential to advance the study of diet patterns.


Assuntos
Diabetes Gestacional/metabolismo , Pré-Eclâmpsia/metabolismo , Resultado da Gravidez , Nascimento Prematuro/metabolismo , Adulto , Diabetes Gestacional/fisiopatologia , Dieta , Feminino , Frutas/metabolismo , Humanos , Aprendizado de Máquina , Masculino , Pré-Eclâmpsia/fisiopatologia , Gravidez , Nascimento Prematuro/fisiopatologia , Fenômenos Fisiológicos da Nutrição Pré-Natal , Estudos Prospectivos , Verduras/metabolismo , Adulto Jovem
20.
Am J Pathol ; 190(5): 970-976, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084366

RESUMO

Preeclampsia (PE) is a hypertensive disease of pregnancy associated with substantial maternal and fetal morbidity and mortality. CORIN is a transmembrane type II serine protease expressed in cardiomyocytes that converts pro-atrial natriuretic peptide into atrial natriuretic peptide, a cardiac hormone that regulates blood pressure. High levels of soluble CORIN have been reported in PE and are supposed to be cardiac in origin. We hypothesized that during pregnancy soluble CORIN is released by the syncytiotrophoblast and that increased levels of soluble CORIN in preeclampsia originate from placenta. A total of 375 patients (181 PE patients and 194 controls) were analyzed. High levels of soluble CORIN were confirmed in maternal blood from preeclamptic pregnancies compared with controls. Differentiated primary villous cytotrophoblasts showed that CORIN was expressed (mRNA and protein levels) and secreted by trophoblastic cells, mostly by the syncytiotrophoblast. Finally, placental explants showed a significant increase in CORIN production and secretion in PE cases compared with controls. This study showed that CORIN is secreted by trophoblastic cells and that high levels of soluble CORIN in preeclampsia have a placental origin.


Assuntos
Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Serina Endopeptidases/biossíntese , Feminino , Humanos , Gravidez , Trofoblastos/metabolismo
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