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1.
FASEB J ; 37(3): e22779, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36723798

RESUMO

Preeclampsia is a gestational disease characterized by two major pathological changes-shallow trophoblast invasion and impaired spiral artery remodeling. Atrial natriuretic peptide (ANP) is a kind of peptide hormone that regulates blood pressure, while the lack of active ANP participates in preeclampsia pathogenesis. However, the underlying mechanism of how ANP modulates trophoblasts function remains unclarified. Here, we performed isobaric tags for relative and absolute quantification (iTRAQ) in ANP-treated HTR-8/SVneo cells and identified Protein Kinase 3 (PKN3) as the downstream factor of ANP, which was downregulated in preeclamptic placenta. Chromatin immunoprecipitation analysis and luciferase assays showed that NFYA was one of the transcription factors for the PKN3 promoter, which was also regulated by ANP treatment in HTR-8/SVneo cells. Transmission electron microscopy and Western Blotting in HTR-8/SVneo cells indicated that ANP inhibited autophagy via AMPK-mTORC1 signaling, while excess autophagy was observed in preeclamptic placenta. The increased expression of PKN3 and enhanced cell invasion ability in HTR-8/SVneo cells induced by ANP could be abolished by autophagy activation or transfection with PKN3 shRNA or NFYA shRNA or NPR-A shRNA via regulating the invasion-related genes and the epithelial mesenchymal transition molecules. Our results demonstrated that ANP could enhance trophoblast invasion by upregulating PKN3 via NFYA promotion through autophagy inhibition in an AMPK/mTORC1 signaling-dependent manner.


Assuntos
Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Pré-Eclâmpsia/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Linhagem Celular , Placenta/metabolismo , Trofoblastos/metabolismo , RNA Interferente Pequeno/metabolismo , Autofagia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Movimento Celular
2.
BMJ ; 380: e072112, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36724989

RESUMO

OBJECTIVE: To examine the associations between five major adverse pregnancy outcomes and long term risks of ischemic heart disease in mothers. DESIGN: National cohort study. SETTING: Sweden. PARTICIPANTS: All 2 195 266 women with a first singleton delivery in Sweden during 1973-2015. MAIN OUTCOME MEASURES: The main outcome measure was incidence of ischemic heart disease from delivery to 2018, identified from nationwide inpatient and outpatient diagnoses. Cox regression was used to calculate hazard ratios for ischemic heart disease associated with preterm delivery, small for gestational age, pre-eclampsia, other hypertensive disorders of pregnancy, and gestational diabetes, adjusting for other adverse pregnancy outcomes and maternal factors. Co-sibling analyses assessed for confounding by shared familial (genetic and environmental) factors. RESULTS: During 53.6 million person years of follow-up, ischemic heart disease was diagnosed in 83 881 (3.8%) women. All five adverse pregnancy outcomes were independently associated with increased risk of ischemic heart disease. In the 10 years after delivery, adjusted hazard ratios for ischemic heart disease associated with specific adverse pregnancy outcomes were 2.09 (95% confidence interval 1.77 to 2.46) for other hypertensive disorders of pregnancy, 1.72 (1.55 to 1.90) for preterm delivery, 1.54 (1.37 to 1.72) for pre-eclampsia, 1.30 (1.09 to 1.56) for gestational diabetes, and 1.10 (1.00 to 1.21) for small for gestational age. The hazard ratios remained significantly increased even 30-46 years after delivery: 1.47 (1.30 to 1.66) for other hypertensive disorders of pregnancy, 1.40 (1.29 to 1.51) for gestational diabetes, 1.32 (1.28 to 1.36) for pre-eclampsia, 1.23 (1.19 to 1.27) for preterm delivery, and 1.16 (1.13 to 1.19) for small for gestational age. These findings were only partially (<45%) explained by shared familial (genetic or environmental) factors. Women who experienced multiple adverse pregnancy outcomes showed further increases in risk (eg, <10 years after delivery, adjusted hazard ratios associated with 1, 2, or ≥3 adverse pregnancy outcomes were 1.29 (1.19 to 1.39), 1.80 (1.59 to 2.03), and 2.26 (1.89 to 2.70), respectively)). CONCLUSIONS: In this large national cohort, women who experienced any of five major adverse pregnancy outcomes showed an increased risk for ischemic heart disease up to 46 years after delivery. Women with adverse pregnancy outcomes should be considered for early preventive evaluation and long term risk reduction to help prevent the development of ischemic heart disease.


Assuntos
Diabetes Gestacional , Hipertensão Induzida pela Gravidez , Isquemia Miocárdica , Pré-Eclâmpsia , Nascimento Prematuro , Gravidez , Recém-Nascido , Feminino , Humanos , Masculino , Resultado da Gravidez/epidemiologia , Mães , Estudos de Coortes , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/diagnóstico , Irmãos , Nascimento Prematuro/epidemiologia , Fatores de Risco , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/etiologia
3.
Sci Rep ; 13(1): 881, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36650223

RESUMO

We recently reported exacerbated endotoxic signs of neuroinflammation and autonomic defects in offspring of preeclamptic (PE) dams. Here, we investigated whether PE programming similarly modifies hemodynamic and renal vasoconstrictor responsiveness to endotoxemia in PE offspring and whether this interaction is modulated by gestational angiotensin 1-7 (Ang1-7). Preeclampsia was induced by gestational treatment with L-NAME. Adult offspring was challenged with lipopolysaccharides (LPS, 5 mg/kg) and systolic blood pressure (SBP) and renal vasoconstrictions were assessed 4 h later. Male, but not female, offspring of PE rats exhibited SBP elevations that were blunted by LPS. Renal vasoconstrictions induced by angiotensin II (Ang II), but not phenylephrine, were intensified in perfused kidneys of either sex. LPS blunted the heightened Ang II responses in male, but not female, kidneys. While renal expressions of AT1-receptors and angiotensin converting enzyme (ACE) were increased in PE offspring of both sexes, ACE2 was upregulated in female offspring only. These molecular effects were diminished by LPS in male offspring. Gestational Ang1-7 caused sex-unrelated attenuation of phenylephrine vasoconstrictions and preferentially downregulated Ang II responses and AT1-receptor and nuclear factor-kB (NFkB) expressions in females. Together, endotoxemia and Ang1-7 offset in sexually-related manners imbalances in renal vasoconstriction and AT1/ACE/ACE2 signaling in PE offspring.


Assuntos
Endotoxemia , Pré-Eclâmpsia , Animais , Feminino , Masculino , Ratos , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Endotoxemia/induzido quimicamente , Endotoxemia/metabolismo , Endotoxinas/metabolismo , Rim/metabolismo , Lipopolissacarídeos/farmacologia , Pré-Eclâmpsia/metabolismo , Sistema Renina-Angiotensina , Vasoconstrição
4.
Cell Mol Life Sci ; 80(2): 44, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36652019

RESUMO

Preeclampsia is a pregnancy-specific cardiovascular disorder, involving significant maternal endothelial dysfunction. Although inappropriate placentation due to aberrant angiogenesis, inflammation and shallow trophoblast invasion are the root causes of preeclampsia, pathogenic mechanisms are poorly understood, particularly in early pregnancy. Here, we first confirm the abnormal expression of important vascular and inflammatory proteins, FK506-binding protein-like (FKBPL) and galectin-3 (Gal-3), in human plasma and placental tissues from women with preeclampsia and normotensive controls. We then employ a three-dimensional microfluidic placental model incorporating human umbilical vein endothelial cells (HUVECs) and a first trimester trophoblast cell line (ACH-3P) to investigate FKBPL and Gal-3 signaling in inflammatory conditions. In human samples, both circulating (n = 17 controls; n = 30 preeclampsia) and placental (n ≥ 6) FKBPL and Gal-3 levels were increased in preeclampsia compared to controls (plasma: FKBPL, p < 0.0001; Gal-3, p < 0.01; placenta: FKBPL, p < 0.05; Gal-3, p < 0.01), indicative of vascular dysfunction in preeclampsia. In our placenta-on-a-chip model, we show that endothelial cells are critical for trophoblast-mediated migration and that trophoblasts effectively remodel endothelial vascular networks. Inflammatory cytokine tumour necrosis factor-α (10 ng/mL) modulates both FKBPL and Gal-3 signaling in conjunction with trophoblast migration and impairs vascular network formation (p < 0.005). Our placenta-on-a-chip recapitulates aspects of inappropriate placental development and vascular dysfunction in preeclampsia.


Assuntos
Placenta , Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Placenta/metabolismo , Galectina 3/genética , Galectina 3/metabolismo , Trofoblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas de Ciclo Celular/metabolismo , Dispositivos Lab-On-A-Chip , Proteínas de Ligação a Tacrolimo/metabolismo
5.
BMC Med ; 21(1): 23, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653824

RESUMO

BACKGROUND: Common pregnancy and perinatal complications are associated with offspring cardiometabolic risk factors. These complications may influence multiple metabolic traits in the offspring and these associations might differ with offspring age. METHODS: We used data from eight population-based cohort studies to examine and compare associations of pre-eclampsia (PE), gestational hypertension (GH), gestational diabetes (GD), preterm birth (PTB), small (SGA) and large (LGA) for gestational age (vs. appropriate size for gestational age (AGA)) with up to 167 plasma/serum-based nuclear magnetic resonance-derived metabolic traits encompassing lipids, lipoproteins, fatty acids, amino acids, ketones, glycerides/phospholipids, glycolysis, fluid balance, and inflammation. Confounder-adjusted regression models were used to examine associations (adjusted for maternal education, parity age at pregnancy, ethnicity, pre/early pregnancy body mass index and smoking, and offspring sex and age at metabolic trait assessment), and results were combined using meta-analysis by five age categories representing different periods of the offspring life course: neonates (cord blood), infancy (mean ages: 1.1-1.6 years), childhood (4.2-7.5 years); adolescence (12.0-16.0 years), and adulthood (22.0-67.8 years). RESULTS: Offspring numbers for each age category/analysis varied from 8925 adults (441 PTB) to 1181 infants (135 GD); 48.4% to 60.0% were females. Pregnancy complications (PE, GH, GD) were each associated with up to three metabolic traits in neonates (P≤0.001) with some evidence of persistence to older ages. PTB and SGA were associated with 32 and 12 metabolic traits in neonates respectively, which included an adjusted standardised mean difference of -0.89 standard deviation (SD) units for albumin with PTB (95% CI: -1.10 to -0.69, P=1.3×10-17) and -0.41 SD for total lipids in medium HDL with SGA (95% CI: -0.56 to -0.25, P=2.6×10-7), with some evidence of persistence to older ages. LGA was inversely associated with 19 metabolic traits including lower levels of cholesterol, lipoproteins, fatty acids, and amino acids, with associations emerging in adolescence, (e.g. -0.11 SD total fatty acids, 95% CI: -0.18 to -0.05, P=0.0009), and attenuating with older age across adulthood. CONCLUSIONS: These reassuring findings suggest little evidence of wide-spread and long-term impact of common pregnancy and perinatal complications on offspring metabolic traits, with most associations only observed for newborns rather than older ages, and for perinatal rather than pregnancy complications.


Assuntos
Diabetes Gestacional , Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Complicações na Gravidez , Nascimento Prematuro , Gravidez , Feminino , Adulto , Adolescente , Recém-Nascido , Humanos , Criança , Lactente , Masculino , Estudos de Coortes , Nascimento Prematuro/etiologia , Complicações na Gravidez/epidemiologia , Lipoproteínas , Ácidos Graxos
6.
Nutrients ; 15(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36678281

RESUMO

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in women. Hypertensive disorders of pregnancy (HDP) affect 5-10% of pregnancies worldwide, and are an independent risk factor for CVD. A greater understanding of the rates of modifiable CVD risk factors in women with a history of HDP can inform CVD prevention priorities in this group. The aim of this study was to understand the rates of individual and multiple modifiable risk factors for CVD (body mass index, fruit and vegetable intake, physical activity, sitting time, smoking, alcohol consumption and depressive symptoms) among women with a history of HDP, and assess whether they differ to women without a history of HDP. This study is a cross-sectional analysis of self-reported data collected for the Australian Longitudinal Study of Women's Health (ALSWH). The sample included 5820 women aged 32-37 years old, who completed survey 7 of the ALSWH in 2015. Women with a history of HDP had a higher multiple CVD modifiable risk factor score compared to those without HDP (mean (SD): 2.3 (1.4) vs. 2.0 (1.3); p < 0.01). HDP history was significantly associated with a higher body mass index (p < 0.01), high-risk alcohol consumption (p = 0.04) and more depressive symptoms (p < 0.01). Understanding that women with a history of HDP have higher CVD risk factors, specifically body mass index, alcohol consumption and depressive symptoms, allows clinicians to provide appropriate and tailored CVD interventions for this group of women.


Assuntos
Doenças Cardiovasculares , Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Adulto , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/diagnóstico , Hipertensão Induzida pela Gravidez/diagnóstico , Estudos Longitudinais , Estudos Transversais , Austrália/epidemiologia , Fatores de Risco , Fatores de Risco de Doenças Cardíacas
7.
BMC Pregnancy Childbirth ; 23(1): 68, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36703104

RESUMO

BACKGROUND: Individuals with hypertensive disorders of pregnancy (HDP) have an elevated lifetime risk of chronic hypertension, metabolic syndrome, and premature cardiovascular disease. Because breastfeeding duration and exclusivity have been associated in observational studies with improved cardiovascular health, optimizing breastfeeding in those with HDP might be an unrealized cardio-prevention approach, in particular because individuals with HDP have more breastfeeding challenges. Breastfeeding supportive interventions targeting one's breastfeeding self-efficacy have been shown to improve breastfeeding rates. METHODS: We designed an open-label, multi-center 1:1 randomized behavioral trial to test whether a previously validated self-efficacy enhancing breastfeeding intervention can improve breastfeeding duration and/or exclusivity, and lower postpartum blood pressure at 12 months. Randomization is computer-generated and stratified by site (four hospitals in Montreal, Quebec and one hospital in Kingston, Ontario; all in Canada). Included are breastfeeding participants with HDP (chronic/gestational hypertension or preeclampsia) who delivered a live singleton infant at > 34 weeks, speak English or French, and have no contraindications to breastfeeding. Informed and written consent is obtained at hospitalization for delivery or a re-admission with hypertension within 1 week of discharge. Participants assigned to the intervention group receive a breastfeeding self-efficacy-based intervention delivered by a trained lactation consultant in hospital, with continued reactive/proactive support by phone or text message for up to 6 months postpartum. Regardless of group assignment, participants are followed for self-reported outcomes, automated office blood pressure, and home blood pressure at several time points with end of follow-up at 12 months. DISCUSSION: This study will assess whether an intensive nurse-led behavioral intervention can improve breastfeeding rates and, in turn, postpartum blood pressure - an early marker for atherosclerotic cardiovascular disease. If effective, this form of enhanced breastfeeding support, along with closer BP and metabolic surveillance, can be implemented broadly in individuals lactating after HDP. TRIAL REGISTRATION: ClinicalTrials.gov, # NCT04580927 , registered on Oct 9, 2020.


Assuntos
Doenças Cardiovasculares , Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Lactente , Gravidez , Feminino , Humanos , Aleitamento Materno , Pressão Sanguínea , Lactação , Autoeficácia , Período Pós-Parto , Ontário , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto
8.
Stroke ; 54(2): 354-363, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36689585

RESUMO

BACKGROUND: Preeclampsia increases the incidence of maternal stroke, a devastating condition that is on the rise. We investigated stroke outcome in a model of experimental preeclampsia with and without treatment with clinically relevant doses of magnesium sulfate (experimental preeclampsia+MgSO4) compared to normal late-pregnant and nonpregnant rats. METHODS: Transient middle cerebral artery occlusion was used to induce focal stroke for either 1.5 or 3 hours. Infarct volume and hemorrhagic transformation were determined as measures of stroke outcome. Changes in core middle cerebral artery and collateral flow were measured by dual laser Doppler. The relationship between middle cerebral artery perfusion deficit and infarction was used as a measure of ischemic tolerance. Oxidative stress and endothelial dysfunction were measured by 3-nitrotyrosine and 8-isoprostane, in brain and serum, respectively. RESULTS: Late-pregnant animals had robust collateral flow and greater ischemic tolerance of brain tissue, whereas experimental preeclampsia had greater infarction that was related to poor collateral flow, endothelial dysfunction, and oxidative stress. Importantly, pregnancy appeared preventative of hemorrhagic transformation as it occurred only in nonpregnant animals. MgSO4 did not provide benefit to experimental preeclampsia animals for infarction. CONCLUSIONS: Stroke outcome was worse in a model of preeclampsia. As preeclampsia increases the risk of future stroke and cardiovascular disease, it is worth understanding the influence of preeclampsia on the material brain and factors that might potentiate injury both during the index pregnancy and years postpartum.


Assuntos
Isquemia Encefálica , Pré-Eclâmpsia , Acidente Vascular Cerebral , Humanos , Gravidez , Feminino , Ratos , Animais , Encéfalo , Infarto da Artéria Cerebral Média , Estresse Oxidativo , Circulação Cerebrovascular , Circulação Colateral
9.
Compr Physiol ; 13(1): 4231-4267, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36715282

RESUMO

Preeclampsia and other hypertensive disorders of pregnancy are major contributors to maternal morbidity and mortality worldwide. This group of disorders includes chronic hypertension, gestational hypertension, preeclampsia, preeclampsia superimposed on chronic hypertension, and eclampsia. The body undergoes important physiological changes during pregnancy to allow for normal placental and fetal development. Several mechanisms have been proposed that may lead to preeclampsia, including abnormal placentation and placental hypoxia, impaired angiogenesis, excessive pro-inflammatory response, immune system imbalance, abnormalities of cellular senescence, alterations in regulation and activity of angiotensin II, and oxidative stress, ultimately resulting in upregulation of multiple mediators of endothelial cell dysfunction leading to maternal disease. The clinical implications of preeclampsia are significant as there are important short-term and long-term health consequences for those affected. Preeclampsia leads to increased risk of preterm delivery and increased morbidity and mortality of both the developing fetus and mother. Preeclampsia also commonly leads to acute kidney injury, and women who experience preeclampsia or another hypertensive disorder of pregnancy are at increased lifetime risk of chronic kidney disease and cardiovascular disease. An understanding of normal pregnancy physiology and the pathophysiology of preeclampsia is essential to develop novel treatment approaches and manage patients with preeclampsia and hypertensive disorders of pregnancy. © 2023 American Physiological Society. Compr Physiol 13:4231-4267, 2023.


Assuntos
Doenças Cardiovasculares , Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Doenças Vasculares , Recém-Nascido , Feminino , Gravidez , Humanos , Pré-Eclâmpsia/tratamento farmacológico , Placenta/irrigação sanguínea , Rim
10.
Funct Integr Genomics ; 23(1): 27, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598700

RESUMO

We aimed to investigate the inhibitory effect of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes (hucMSC-Exos) transmitting microRNA-342-5p (miR-342-5p) on the development of preeclampsia (PE) by targeting programmed cell death 4 (PDCD4). The primary hucMSCs were cultured and transfected with miR-342-5p, and the exosomes (Exo) were extracted from the hucMSCs. PE rats were performed with an intraperitoneal injection of L-NAME from days 11 to 19 of gestation, and injection of Exo, Exo-negative control (NC), Exo-miR-342-5p agomir, Exo-miR-342-5p antagomir, and overexpressing PDCD4 (oe-PDCD4) vector into the placenta on the 16th day of pregnancy. HE staining was utilized to observe the pathological changes in placental tissues. TUNEL staining was implemented to evaluate cell apoptosis in placental tissues. Blood pressure and 24-h urinary protein in pregnant rats were measured by a non-invasive rat tail artery blood pressure measurement and protein auto-analyzer. Expressions of miR-342-5p, PDCD4, proinflammatory cytokines (TNF-α and IL-1ß), and anti-inflammatory cytokines (IL-10 and TGF-ß) were detected by RT-qPCR, and PDCD4 protein expression was determined by Western blot. The interaction between miR-342-5p and PDCD4 was analyzed by luciferase activity assay. MiR-342-5p was downregulated while PDCD4 was upregulated in the placental tissues of PE rats. HucMSC-Exo relieved pathology and suppressed inflammatory response, and apoptosis in the placental tissues, as well as reducing blood pressure and 24-h urinary protein of PE rats. Elevated miR-342-5p enhanced the promoting influence of hucMSC-Exo on PE rats, while inhibited miR-342-5p reversed the functions of hucMSC-Exo on PE rats. miR-342-5p targeted PDCD4. Overexpression of PDCD4 worsened the development of PE in rats. HucMSC-Exo conveying elevated miR-342-5p inhibits the development of PE in a rat model through downregulating PDCD4.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Pré-Eclâmpsia , Humanos , Ratos , Feminino , Gravidez , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Placenta/metabolismo , Citocinas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Cordão Umbilical/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo
11.
Sci Rep ; 13(1): 153, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36599871

RESUMO

Pre-eclampsia is associated with postnatal cardiac dysfunction; however, the nature of this relationship remains uncertain. This multicentre retrospective cohort study aimed to determine the prevalence of pre-eclampsia in women with pre-existing cardiac dysfunction (left ventricular ejection fraction < 55%) and explore the relationship between pregnancy outcome and pre-pregnancy cardiac phenotype. In this cohort of 282 pregnancies, pre-eclampsia prevalence was not significantly increased (4.6% [95% C.I 2.2-7.0%] vs. population prevalence of 4.6% [95% C.I. 2.7-8.2], p = 0.99); 12/13 women had concurrent obstetric/medical risk factors for pre-eclampsia. The prevalence of preterm pre-eclampsia (< 37 weeks) and fetal growth restriction (FGR) was increased (1.8% vs. 0.7%, p = 0.03; 15.2% vs. 5.5%, p < 0.001, respectively). Neither systolic nor diastolic function correlated with pregnancy outcome. Antenatal ß blockers (n = 116) were associated with lower birthweight Z score (adjusted difference - 0.31 [95% C.I. - 0.61 to - 0.01], p = 0.04). To conclude, this study demonstrated a modest increase in preterm pre-eclampsia and significant increase in FGR in women with pre-existing cardiac dysfunction. Our results do not necessarily support a causal relationship between cardiac dysfunction and pre-eclampsia, especially given the population's background risk status. The mechanism underpinning the relationship between cardiac dysfunction and FGR merits further research but could be influenced by concomitant ß blocker use.


Assuntos
Cardiomiopatias , Cardiopatias , Pré-Eclâmpsia , Humanos , Gravidez , Feminino , Pré-Eclâmpsia/epidemiologia , Resultado da Gravidez , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda , Retardo do Crescimento Fetal/epidemiologia , Cardiomiopatias/complicações , Cardiomiopatias/epidemiologia
12.
Cell Transplant ; 32: 9636897221145682, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593749

RESUMO

We aimed to explore whether the effect of progesterone on preeclampsia via the PI3K/AKT signaling pathway. First, we studied the role of progesterone in preeclampsia patients and HTR-8/Svneo cells by adding progesterone. Then PI3K inhibitor LY294002 was added. The effects of progesterone on preeclampsia were also studied in animals by constructing a preeclampsia rat model. CCK-8 and Transwell assay were applied to measure cell viability and invasion ability. ELISA was performed to measure progesterone, MMP-2, MMP-9, pro-inflammatory factors TNF-α, IL-1ß, and anti-inflammatory factors IL-4, IL-10, and IL-13 levels. HE staining was used to detect the pathological changes in uterine spiral artery. Western blot was performed to detect Cyclin D1, PCNA, MMP-2, MMP-9, inflammatory factors TNF-α, IL-1ß, IL-4, IL-10, IL-13, and PI3K/AKT signaling pathway related proteins AKT, p-AKT, PI3K, and p-PI3K expressions. Progesterone could reduce blood pressure and urine protein in pregnant women with preeclampsia. TNF-α and IL-1ß levels were decreased, but IL-4, IL-10, IL-13, cyclin D1, and PCNA levels were increased in pregnant women with preeclampsia after using progesterone. After the use of progesterone, the symptoms of the PE model group were improved. Among them, the lumen of the placental uterine spiral artery was enlarged, and the fibrinoid necrosis of the uterine wall and acute atherosclerotic lesions were relieved. In addition, progesterone promoted HTR-8/Svneo cells proliferation and invasion. However, high expression of MMP-2, MMP-9, p-AKT, and p-PI3K in Normal and preeclampsia groups caused by progesterone was weakened after adding LY294002, indicating that progesterone could activate PI3K/AKT signaling pathway to regulate HTR-8/Svneo cells. Progesterone decreased urine protein and blood pressure of preeclampsia rats in a concentration-dependent manner. Moreover, progesterone activated the PI3K/AKT signaling pathway and inhibited the inflammatory response in preeclampsia rats.


Assuntos
Pré-Eclâmpsia , Trofoblastos , Feminino , Gravidez , Humanos , Ratos , Animais , Trofoblastos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Progesterona/farmacologia , Placenta/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Ciclina D1/metabolismo , Interleucina-10/metabolismo , Pré-Eclâmpsia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Transdução de Sinais/fisiologia , Movimento Celular
13.
Lancet Healthy Longev ; 4(1): e34-e42, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36610446

RESUMO

BACKGROUND: Hypertensive disorders of pregnancy are associated with cardiovascular disease later in life. Given that hypertensive disorders of pregnancy often occur at a relatively young age, there might be an opportunity to use preventive measures to reduce the risk of early cardiovascular disease and mortality. The aim of this study was to assess the risk of cardiovascular mortality in women after a hypertensive disorder of pregnancy. METHODS: In this population-based cohort study, the Netherlands Perinatal Registry (PRN) and the national death registry at the Dutch Central Bureau for Statistics were linked. We analysed women in the Netherlands with a first birth during 1995-2015 to determine the association between cardiovascular mortality and hypertensive disorders of pregnancy (based on recorded diastolic blood pressure or proteinuria, or both). We analysed the association between the highest diastolic blood pressure measured in pregnancy and cardiovascular mortality and constructed survival curves to assess cardiovascular mortality after hypertensive disorders of pregnancy, specifically pre-eclampsia and gestational hypertension. To differentiate between the severity of hypertensive disorders of pregnancy, cardiovascular mortality was assessed in women with a combination of hypertensive disorders of pregnancy with preterm birth (gestational age <37 weeks) and growth restriction (birthweight in the 10th percentile or less). All hazard ratios (HRs)were adjusted for maternal age. FINDINGS: Between Jan 1, 1995, and Dec 31, 2015, the PRN contained 2 462 931 deliveries and 1 625 246 women. In 1 243 890 women data on their first pregnancy were available and were included in this analysis after linkage, with a median follow-up time of 11·2 years (IQR 6·1-16·3). 259 177 (20·8%) women had hypertensive disorders of pregnancy, and of these 45 482 (3·7%) women had pre-eclampsia and 213 695 (17·2%) women had gestational hypertension; 984 713 (79·2%) women did not develop hypertension in their first pregnancy. Compared with women without hypertensive disorders of pregnancy, the risk of death from any cause was higher in women who had hypertensive disorders (HR 1·30 [95% CI 1·23-1·37], p<0·001), pre-eclampsia (1·65 [1·48-1·83]; p<0·0001), and gestational hypertension (1·23 [1·16-1·30]; p<0·0001). Those women with pre-eclampsia had a higher risk of cardiovascular mortality compared with those without any hypertensive disorders of pregnancy (adjusted HR 3·39 [95% CI 2·67-4·29]), as did those with gestational hypertension (2·22 [1·91-2·57]). For women with a history of hypertensive disorders of pregnancy combined with preterm birth (gestational age <37 weeks) and birthweight in the 10th percentile or less, the adjusted HR for cardiovascular mortality was 6·43 (95% CI 4·36-9·47), compared with women without a hypertensive disorder of pregnancy. The highest diastolic blood pressure measured during pregnancy was the strongest risk factor for cardiovascular mortality (for 80-89 mm Hg: adjusted HR 1·47 [95% CI 1·00-2·17]; for 130 mm Hg and higher: 14·70 [7·31-29·52]). INTERPRETATION: Women with a history of hypertensive disorders of pregnancy have a risk of cardiovascular mortality that is 2-3 times higher than that of women with normal blood pressure during pregnancy. The highest measured diastolic blood pressure during pregnancy is an important predictor for cardiovascular mortality later in life; therefore, women who have hypertensive disorders of pregnancy should be given personalised cardiovascular follow-up plans to reduce their risk of cardiovascular mortality. FUNDING: None.


Assuntos
Doenças Cardiovasculares , Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Nascimento Prematuro , Gravidez , Feminino , Humanos , Masculino , Pré-Eclâmpsia/prevenção & controle , Estudos de Coortes , Nascimento Prematuro/epidemiologia , Peso ao Nascer , Países Baixos/epidemiologia
14.
J Matern Fetal Neonatal Med ; 36(1): 2160627, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36597834

RESUMO

OBJECTIVE: The rate of preeclampsia with severe features has increased. Previous studies have shown elevated liver enzymes are an indicator of worsening hypertensive disease of pregnancy and adverse outcomes, therefore leading to their inclusion as a diagnostic criterion for severe features of preeclampsia. Despite this, there are limited data to support an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) concentration ≥ two times the upper limit of normal as the critical point at which maternal harm from ongoing pregnancy exceeds neonatal harm from delivery. The objective of this study is to evaluate the association between elevated liver enzymes and maternal and neonatal outcomes among patients with preeclampsia with severe features. METHODS: Retrospective cohort study among hypertensive patients who delivered ≥23 weeks' gestation at Oregon Health & Science University (October 2013-September 2018). Those with preeclampsia with severe features (including chronic hypertension with superimposed preeclampsia meeting criteria for severe features) were included after a screening of ICD-9 and ICD-10 codes and chart validation. The primary exposure was elevated liver enzymes prior to delivery, according to the American College of Obstetricians and Gynecologists' criteria for severe features of preeclampsia: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2x the upper limit of normal (above threshold liver function tests [LFTs]). Primary outcomes included adverse maternal and neonatal outcomes. Differences were analyzed by Chi-squared, Fisher's exact, t-test, and logistic regression, with α = 0.05. RESULTS: Of 11,825 deliveries, 319 (2.7%) met inclusion criteria and had preeclampsia with severe features. Of these, 44 (13.8%) had above threshold LFTs. Adverse maternal outcomes were no different in those with above threshold LFTs compared to those with below threshold LFTs. The unadjusted odds of an adverse neonatal outcome were 2.08 times greater in patients with above threshold LFTs (95% CI: 1.04-4.14), and 2.43 times greater when adjusting for maternal characteristics (95% CI: 1.17-5.04) compared to those with below threshold LFTs. However, the association between above threshold LFTs and adverse neonatal outcomes became non-significant after adjustment for gestational age at delivery (OR: 1.54, 95% CI: 0.63-3.76). CONCLUSION: Among patients with preeclampsia with severe features, above threshold LFTs are not independently associated with an increased risk of adverse maternal or neonatal outcomes. Adverse neonatal outcomes in patients with preeclampsia with severe features and above threshold LFTs are driven by earlier gestational age at delivery. Prospective studies are needed to guide delivery timing in patients with preeclampsia and elevated liver enzymes. BRIEF RATIONALE: The criteria for elevated liver function tests (greater than two times the upper limit of normal) are widely accepted among obstetricians to diagnose a severe feature of preeclampsia. However, these criteria are based on expert opinion and extrapolated from data on patients with HELLP syndrome. Since preterm delivery of the neonate is recommended for preeclampsia with severe features, the threshold used to define severe liver enzyme elevation has a direct impact on neonatal outcomes. Therefore, the goal of our study was to determine if patients with preeclampsia with severe features and a pre-delivery AST or ALT level ≥ two times the upper limit of normal have worse maternal and neonatal outcomes compared to those with an AST and ALT below this level.


Assuntos
Hipertensão , Pré-Eclâmpsia , Gravidez , Recém-Nascido , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Estudos Retrospectivos , Alanina Transaminase , Aspartato Aminotransferases , Fígado
15.
Arch Immunol Ther Exp (Warsz) ; 71(1): 3, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681768

RESUMO

Preeclampsia and HIV are a significant burden to maternal health globally, especially in low-middle income countries such as South Africa. In the KwaZulu-Natal province, SA antenatal HIV prevalence is 41.1%, while PE is 12%. PE and HIV infections are maternal stress and inflammation that impact placental function and fetal development. Therefore, this study investigated the impact of the comorbidity of PE and HIV on placental stress and neurodevelopment. Placentae were obtained from four cohorts of pregnant women: normotensive HIV negative, normotensive HIV positive, preeclamptic HIV negative, and preeclamptic HIV positive. The placental tissue sections were immunostained for OGT and T4. Our findings showed that the maternal weight, diastolic, and systolic blood pressures (BP) were higher in PE vs. the normotensive groups, irrespective of HIV status. In addition, significant changes were noticed in the placental weight, fetoplacental ratio, and placental efficiency coefficient. Our findings showed that the maternal weight, diastolic, and systolic blood pressures (BP) were statistically higher in the PE compared to the normotensive. No significant differences were observed between HIV positive and HIV negative groups. In addition, significant changes were noticed in the placental weight, fetoplacental ratio, and placental coefficient. Furthermore, considerable upregulation in the placental expression of OGT in both the conducting and exchange villi of PE and concomitant downregulation in HIV-positive patients compared with Normotensive and HIV-negative individuals, respectively. Our results provide inferential evidence on the dysregulation of OGT in the comorbidity of PE and HIV. This may mediate a compromised programmed outcome of an adverse maternal environment during pregnancy and consequently affect fetal development.


Assuntos
Infecções por HIV , Pré-Eclâmpsia , Feminino , Gravidez , Humanos , Placenta , Pré-Eclâmpsia/metabolismo , África do Sul/epidemiologia
16.
Curr Opin Nephrol Hypertens ; 32(2): 153-164, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36683540

RESUMO

PURPOSE OF REVIEW: Hypertensive disorders of pregnancy remain a highly morbid condition that affects both the mother and fetus, complicate approximately 10% of pregnancies worldwide, and contribute to immediate and long-term cardiovascular outcomes. There is still much to learn regarding pathogenesis and treatment goals. RECENT FINDINGS: There is updated information on the pathogenesis of preeclampsia and treatment thresholds for HTN in pregnancy. l-Kynurenine, a metabolite of the essential amino acid l-tryptophan, has been implicated in preeclampsia as decreased levels were found in a uninephrectomized pregnant mouse model of preeclampsia, where replacement of l-kynurenine rescued the preeclamptic state. Further, data from CHIPS (The Control of HTN in Pregnancy Study) and CHAP (Chronic HTN and Pregnancy) trials demonstrate not only the safety of lowering blood pressure to either a diastolic goal of 85 mmHg (CHIPS) or less than 160/105 mmHg (CHAP) without detriment to the fetus but the CHAPS trial has also shown a decrease in the rate of preeclampsia in the treatment group. SUMMARY: We will summarize the different types of hypertensive disorders in pregnancy, updates on the pathogenesis of preeclampsia, and appropriate HTN management based on the latest evidence in order to better care for mother and child.


Assuntos
Hipertensão , Pré-Eclâmpsia , Gravidez , Feminino , Animais , Camundongos , Humanos , Pré-Eclâmpsia/terapia , Cinurenina , Hipertensão/tratamento farmacológico , Feto
17.
Curr Opin Nephrol Hypertens ; 32(2): 124-133, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36683536

RESUMO

PURPOSE OF REVIEW: This review will summarize recent findings relating to the diagnostic approach to preeclampsia and current avenues of research aimed at modifying the underlying disease process. RECENT FINDINGS: Growing international consensus supports a broad preeclampsia definition that incorporates maternal end-organ and uteroplacental dysfunction. Recent evidence demonstrates that this definition better identifies women and babies at risk of adverse outcomes compared to the traditional definition of hypertension and proteinuria. Multiple studies have demonstrated the usefulness and cost-effectiveness of angiogenic biomarkers such as soluble fms-like tyrosine kinase-1 and placental growth factor as a clinical adjunct to diagnose and predict severity of preeclampsia associated outcomes. Current novel therapeutic approaches to preeclampsia target pathogenic pathways (e.g. antiangiogenesis) or downstream effects such as oxidative stress and nitric oxide. Recent findings relating to these promising candidates are discussed. Multicenter clinical trials are needed to evaluate their effectiveness and ability to improve fetal and maternal outcomes. SUMMARY: We provide an updated framework of the current approaches to define and diagnose preeclampsia. Disease modifying therapies (in particular, targeting the angiogenic pathway) are being developed for the first time and promise to revolutionize the way we manage preeclampsia.


Assuntos
Hipertensão , Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/terapia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator de Crescimento Placentário , Biomarcadores/metabolismo , Estudos Multicêntricos como Assunto
18.
BMC Pregnancy Childbirth ; 23(1): 42, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658509

RESUMO

BACKGROUND: Delayed diagnosis of preeclampsia contributes to maternal morbidity and mortality. Patient-performed home blood pressure monitoring facilitates more frequent monitoring and earlier diagnosis. However, challenges may exist to implementation in low- and middle income-countries. METHODS: This cross-sectional mixed methods study evaluated obstetric doctors' perspectives on the benefits of and barriers to the implementation of home blood pressure monitoring among pregnant women in Ghana. Participants were doctors providing obstetric care at Korle Bu Teaching Hospital. Electronic surveys were completed by 75 participants (response rate 49.3%), consisting of demographics and questions on attitudes and perceived benefits and challenges of home BP monitoring. Semi-structured interviews were completed by 22 participants to expand on their perspectives. RESULTS: Quantitative and qualitative results converged to highlight that the current state of blood pressure monitoring among pregnant women in Ghana is inadequate. The majority agreed that delayed diagnosis of preeclampsia leads to poor health outcomes in their patients (90.6%, n = 68) and earlier detection would improve outcomes (98.7%, n = 74). Key qualitative benefits to the adoption of home blood pressure monitoring were patient empowerment and trust of diagnosis, more quantity and quality of blood pressure data, and improvement in systems-level efficiency. The most significant barriers were the cost of monitors, lack of a communication system to convey abnormal values, and low health literacy. Overall, doctors felt that most barriers could be overcome with patient education and counseling, and that benefits far outweighed barriers. The majority of doctors (81.3%, n = 61), would use home BP data to inform their clinical decisions and 89% (n = 67) would take immediate action based on elevated home BP values. 91% (n = 68) would recommend home BP monitoring to their pregnant patients. CONCLUSION: Obstetric doctors in Ghana strongly support the implementation of home blood pressure monitoring, would use values to inform their clinical management, and believe it would improve patient outcomes. Addressing the most significant barriers, including cost of blood pressure monitors, lack of a communication system to convey abnormal values, and need for patient education, is essential for successful implementation.


Assuntos
Monitorização Ambulatorial da Pressão Arterial , Pré-Eclâmpsia , Humanos , Gravidez , Feminino , Centros de Atenção Terciária , Gana , Pré-Eclâmpsia/diagnóstico , Estudos Transversais , Pressão Sanguínea
19.
PLoS One ; 18(1): e0280256, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36689404

RESUMO

Pathophysiology of pre-eclampsia depends on a defective trophoblastic invasion of uteroplacental blood vessels that leads to placental ischemia and induction of an inflammatory process within the placenta. This process may trigger the expression of Cancer antigen 125 (CA 125), C-reactive protein (CRP) and uric acid (UA). This research aimed to evaluate the association of serum CA 125, CRP and uric acid with Preeclampsia. The study recruited 200 singleton Sudanese pregnant women, who were divided into three groups: controls (n = 100), mild preeclampsia (n = 46) and severe preeclampsia (n = 54). The study subjects were matched for maternal age, gestational age and body mass index. Blood samples were taken for measurement of the different variables using immune- assay and enzymatic automated chemical analysis. The levels of CA 125 in mild and severe preeclampsia were (21.94±0.749 IU/ml) and (40.78±1.336 IU/ml) respectively, which was significantly different (P<0.001) from the control mean (16.48±0.584 IU/ml). There was also a significant difference between the mean levels of CRP in mild and severe preeclampsia (15.17±0.788 mg/L), (31.50±1.709 mg/L) compared with controls (4.79±0.178 mg/L), (P<0.01). There was also a significant difference in the mean levels of UA in mild and severe cases (6.44±0.293 and7.37±0.272) in comparison with the controls (4.00±0.061); (P<0.001). There were significant differences between severe and mild groups (P<0.05). Cancer antigen 125, CRP and UA levels correlated positively with mean arterial blood pressure (MAP) where (r >0.7; P < 0.001). ROC curve validates the utility of these biomarkers for monitoring preeclampsia (AUC >0.8; P < 0.001). In conclusion CA 125, CRP and UA were significantly higher in preeclampsia compared with the controls. The rise of the analytes was directly associated with the severity of the disease.


Assuntos
Neoplasias , Pré-Eclâmpsia , Feminino , Gravidez , Humanos , Proteína C-Reativa/metabolismo , Ácido Úrico , Antígeno Ca-125 , Placenta/metabolismo , Sudão , Estudos de Casos e Controles , Neoplasias/metabolismo , Mediadores da Inflamação/metabolismo
20.
Curr Opin Nephrol Hypertens ; 32(2): 118-123, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36598435

RESUMO

PURPOSE OF REVIEW: Endothelial dysfunction is a major risk factor for many cardiovascular diseases, notably hypertension. Obesity increases the risk of endothelial dysfunction in association with increasing production of the adipokine leptin. Preclinical studies have begun to unravel the mechanisms whereby leptin leads to the development of endothelial dysfunction, which are sex-specific. This review will summarize recent findings of mechanisms of leptin-induced endothelial impairment in both male and females and in pregnancy. RECENT FINDINGS: Leptin receptors are found in high concentrations in the central nervous system (CNS), via which leptin promotes appetite suppression and upregulates sympathetic nervous system activation. However, leptin receptors are expressed in many other tissues, including the vascular endothelial cells and smooth muscle cells. Recent studies in mice with vascular endothelial or smooth muscle-specific knockdown demonstrate that endothelial leptin receptor activation plays a protective role against endothelial dysfunction in male animals, but not necessarily in females. Clinical studies indicate that women may be more sensitive to obesity-associated vascular endothelial dysfunction. Emerging preclinical data indicates that leptin and progesterone increase aldosterone production and endothelial mineralocorticoid receptor activation, respectively. Furthermore, decades of clinical studies indicate that leptin levels increase in the hypertensive pregnancy disorder preeclampsia, which is characterized by systemic endothelial dysfunction. Leptin infusion in mice induces the clinical characteristics of preeclampsia, including endothelial dysfunction. SUMMARY: Novel preclinical data indicate that the mechanisms whereby leptin promotes endothelial dysfunction are sex-specific. Leptin-induced endothelial dysfunction may also play a role in hypertensive pregnancy as well.


Assuntos
Hipertensão , Pré-Eclâmpsia , Masculino , Feminino , Humanos , Camundongos , Animais , Leptina , Células Endoteliais , Receptores para Leptina , Obesidade/complicações
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