RESUMO
Preeclampsia (PE) is a multifactorial pregnancy disorder characterized by hypertension and proteinuria, posing significant risks to both maternal and fetal health. Despite extensive research, its complex pathophysiology remains incompletely understood. This narrative review aims to elucidate the intricate mechanisms contributing to PE, focusing on abnormal placentation, maternal systemic response, oxidative stress, inflammation, and genetic and epigenetic factors. This review synthesizes findings from recent studies, clinical trials, and meta-analyses, highlighting key molecular and cellular pathways involved in PE. The review integrates data on oxidative stress biomarkers, angiogenic factors, immune interactions, and mitochondrial dysfunction. PE is initiated by poor placentation due to inadequate trophoblast invasion and improper spiral artery remodeling, leading to placental hypoxia. This triggers the release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), causing widespread endothelial dysfunction and systemic inflammation. Oxidative stress, mitochondrial abnormalities, and immune dysregulation further exacerbate the condition. Genetic and epigenetic modifications, including polymorphisms in the Fms-like tyrosine kinase 1 (FLT1) gene and altered microRNA (miRNA) expression, play critical roles. Emerging therapeutic strategies targeting oxidative stress, inflammation, angiogenesis, and specific molecular pathways like the heme oxygenase-1/carbon monoxide (HO-1/CO) and cystathionine gamma-lyase/hydrogen sulfide (CSE/H2S) pathways show promise in mitigating preeclampsia's effects. PE is a complex disorder with multifactorial origins involving abnormal placentation, endothelial dysfunction, systemic inflammation, and oxidative stress. Despite advances in understanding its pathophysiology, effective prevention and treatment strategies remain limited. Continued research is essential to develop targeted therapies that can improve outcomes for both mothers and their babies.
Assuntos
Estresse Oxidativo , Pré-Eclâmpsia , Humanos , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/metabolismo , Gravidez , Feminino , Epigênese Genética , Inflamação/metabolismo , Biomarcadores , Placenta/metabolismo , Placenta/fisiopatologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
Purpose: To investigate the role of hypoxia-inducible transcription factor-1 alpha (HIF-1α) and angiogenetic factor endothelin-1 (ET-1) expression in regulating hypoxia and placental development by routine histopathological methods. Methods: Twenty preeclamptic and normal placentas were used. Placenta tissue pieces were examined histopathologically after routine paraffin follow-ups. HIF-1α and ET-1 proteins were examined immunohistochemically, and placental tissues were examined ultrastructurally. Results: Increase in syncytial proliferation, endothelial damage in vessels, and increase in collagen were observed in preeclamptic placentas. As a result of preeclampsia, an increase was observed in HIF-1α and ET-1 protein levels in the placenta. Dilatation of endoplasmic reticulum and loss of cristae in mitochondria were observed in trophoblast cells in preeclamptic placental sections. Conclusion: High regulation of oxygen resulting from preeclampsia has been shown to be a critical determinant of placentagenesis and plays an important role in placental differentiation, changes in maternal and fetal blood circulation, trophoblastic invasion, and syncytial node increase. It has been thought that preeclampsia affects secretion by disrupting the endoplasmic reticulum structure and induces mitochondrial damage, and that ET-1 may potentially help in the induction of stress pathways as a result of hypoxia in preeclampsia.
Assuntos
Placenta/fisiopatologia , Doenças Placentárias , Pré-Eclâmpsia , Endotelinas , Subunidade alfa do Fator 1 Induzível por Hipóxia , Imuno-HistoquímicaRESUMO
OBJECTIVE: In addition to the lungs, the placenta and the endothelium can be affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are markers of endothelial dysfunction and could potentially serve as predictors of severe coronavirus disease 2019 (COVID-19). We aimed to investigate the association of serum concentrations of sFlt-1 and PlGF with the severity of COVID-19 in pregnancy. METHODS: This was a prospective cohort study carried out in a tertiary care hospital in Mexico City, Mexico. Symptomatic pregnant women with a positive reverse-transcription quantitative polymerase chain reaction test for SARS-CoV-2 infection who fulfilled the criteria for hospitalization were included. The primary outcome was severe pneumonia due to COVID-19. Secondary outcomes were intensive care unit (ICU) admission, viral sepsis and maternal death. sFlt-1 levels were expressed as multiples of the median (MoM). The association between sFlt-1 and each adverse outcome was explored by logistic regression analysis, adjusted for gestational age for outcomes occurring in more than five patients, and the predictive performance was assessed by receiver-operating-characteristics-curve analysis. RESULTS: Among 113 pregnant women with COVID-19, higher sFlt-1 MoM was associated with an increased probability of severe pneumonia (adjusted odds ratio (aOR), 1.817 (95% CI, 1.365-2.418)), ICU admission (aOR, 2.195 (95% CI, 1.582-3.047)), viral sepsis (aOR, 2.318 (95% CI, 1.407-3.820)) and maternal death (unadjusted OR, 5.504 (95% CI, 1.079-28.076)). At a 10% false-positive rate, sFlt-1 MoM had detection rates of 45.2%, 66.7%, 83.3% and 100% for severe COVID-19 pneumonia, ICU admission, viral sepsis and maternal death, respectively. PlGF values were similar between women with severe and those with non-severe COVID-19 pneumonia. CONCLUSION: sFlt-1 MoM is higher in pregnant women with severe COVID-19 and has the capability to predict serious adverse pregnancy events, such as severe pneumonia, ICU admission, viral sepsis and maternal death. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
Assuntos
COVID-19 , Unidades de Terapia Intensiva/estatística & dados numéricos , Pneumonia Viral , Complicações Infecciosas na Gravidez , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/terapia , Estudos de Coortes , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Idade Gestacional , Humanos , México/epidemiologia , Mortalidade , Placenta/metabolismo , Placenta/fisiopatologia , Fator de Crescimento Placentário/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/etiologia , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/terapia , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de DoençaRESUMO
Placental pathophysiology in SARS-CoV-2 infection can help researchers understand more about the infection and its impact on the maternal/neonatal outcomes. This brief review provides an overview about some aspects of the placental pathology in SARS-CoV-2 infection. In total, 11 papers were included. The current literature suggests that there are no specific histopathological characteristics in the placenta related to SARS-CoV-2 infection, but placentas from infected women are more likely to show findings of maternal and/or fetal malperfusion. The most common findings in placentas from infected women were fibrin deposition and intense recruitment of inflammatory infiltrates. The transplacental transmission of this virus is unlikely to occur, probably due to low expression of the receptor for SARS-CoV-2 in placental cell types. Further studies are needed to improve our knowledge about the interaction between the virus and the mother-fetus dyad and the impact on maternal and neonatal/fetal outcomes.
A fisiopatologia da placenta na infecção por SARS-CoV-2 pode ajudar os pesquisadores a entender mais sobre a infecção e seu impacto nos resultados maternos/neonatais. Esta revisão breve fornece uma visão geral sobre alguns aspectos da patologia placentária na infecção por SARS-CoV-2. Ao todo, 11 artigos foram incluídos. A literatura atual sugere que não há características histopatológicas específicas nas placentas relacionadas à infecção por SARS-CoV-2, mas as placentas de mulheres infectadas têm maior probabilidade de apresentar achados de má perfusão materna e/ou fetal. Os achados mais comuns em placentas de mulheres infectadas foram deposição de fibrina e intenso recrutamento de infiltrado inflamatório. A transmissão transplacentária deste vírus é improvável, devido à baixa expressão do receptor para SARS-CoV-2 em tipos de células da placenta. Mais estudos são necessários para melhorar nosso conhecimento sobre a interação entre o vírus e a díade mãe-feto e o impacto nos resultados maternos e neonatais/fetais.
Assuntos
COVID-19/patologia , Placenta/patologia , Complicações Infecciosas na Gravidez/patologia , COVID-19/fisiopatologia , COVID-19/virologia , Feminino , Humanos , Transmissão Vertical de Doenças Infecciosas , Placenta/irrigação sanguínea , Placenta/fisiopatologia , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/fisiopatologia , Complicações Infecciosas na Gravidez/virologiaRESUMO
Abstract Placental pathophysiology in SARS-CoV-2 infection can help researchers understand more about the infection and its impact on thematernal/neonatal outcomes. This brief review provides an overview about some aspects of the placental pathology in SARSCoV- 2 infection. In total, 11 papers were included. The current literature suggests that there are no specific histopathological characteristics in the placenta related to SARSCoV- 2 infection, but placentas frominfected women aremore likely to show findings of maternal and/or fetal malperfusion. The most common findings in placentas from infected women were fibrin deposition and intense recruitment of inflammatory infiltrates. The transplacental transmission of this virus is unlikely to occur, probably due to low expression of the receptor for SARS-CoV-2 in placental cell types. Further studies are needed to improve our knowledge about the interaction between the virus and the mother-fetus dyad and the impact on maternal and neonatal/fetal outcomes.
Resumo A fisiopatologia da placenta na infecção por SARS-CoV-2 pode ajudar os pesquisadores a entender mais sobre a infecção e seu impacto nos resultados maternos/neonatais. Esta revisão breve fornece uma visão geral sobre alguns aspectos da patologia placentária na infecção por SARS-CoV-2. Ao todo, 11 artigos foram incluídos. A literatura atual sugere que não há características histopatológicas específicas nas placentas relacionadas à infecção por SARS-CoV-2, mas as placentas de mulheres infectadas têm maior probabilidade de apresentar achados de má perfusão materna e/ou fetal. Os achados mais comuns em placentas de mulheres infectadas foram deposição de fibrina e intenso recrutamento de infiltrado inflamatório. A transmissão transplacentária deste vírus é improvável, devido à baixa expressão do receptor para SARS-CoV-2 em tipos de células da placenta. Mais estudos são necessários para melhorar nosso conhecimento sobre a interação entre o vírus e a díade mãe-feto e o impacto nos resultados maternos e neonatais/fetais.
Assuntos
Humanos , Feminino , Gravidez , Placenta/patologia , Complicações Infecciosas na Gravidez/patologia , COVID-19/patologia , Placenta/fisiopatologia , Placenta/irrigação sanguínea , Placenta/virologia , Complicações Infecciosas na Gravidez/fisiopatologia , Complicações Infecciosas na Gravidez/virologia , Transmissão Vertical de Doenças Infecciosas , COVID-19/fisiopatologia , COVID-19/virologiaRESUMO
Prenatal exposure to glucocorticoids (GC) is a central topic of interest in medicine since GCs are essential for the maturation of fetal organs and intrauterine growth. Synthetic glucocorticoids, which are used in obstetric practice, exert beneficial effects on the fetus, but have also been reported to lead to intrauterine growth retardation (IUGR). In this study, a model of growth restriction in mice was established through maternal administration of dexamethasone during late gestation. We hypothesised that GC overexposure may adversely affect placental angiogenesis and fetal and placental growth. Female BALB/c mice were randomly assigned to control or dexamethasone treatment, either left to give birth or euthanised on days 15, 16, 17 and 18 of gestation followed by collection of maternal and fetal tissue. The IUGR rate increased to 100% in the dexamethasone group (8 mg/kg body weight on gestational days 14 and 15) and pups had clinical features of symmetrical IUGR at birth. Dexamethasone administration significantly decreased maternal body weight gain and serum corticosterone levels. Moreover, prenatal dexamethasone treatment not only induced fetal growth retardation but also decreased placental weight. In IUGR placentas, VEGFA protein levels and mRNA expression of VEGF receptors were reduced and NOS activity was lower. Maternal dexamethasone administration also reduced placental expression of the GC receptor, αGR. We demonstrated that maternal dexamethasone administration causes fetal and placental growth restriction. Furthermore, we propose that the growth retardation induced by prenatal GC overexposure may be caused, at least partially, by an altered placental angiogenic profile.
Assuntos
Dexametasona , Retardo do Crescimento Fetal/metabolismo , Placenta/metabolismo , Placentação , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/fisiopatologia , Regulação da Expressão Gênica no Desenvolvimento , Idade Gestacional , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Placenta/fisiopatologia , Gravidez , Receptores de Glucocorticoides/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genéticaAssuntos
Diabetes Gestacional , Obesidade Materna , Animais , Glicemia/metabolismo , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/metabolismo , Diabetes Gestacional/fisiopatologia , Diabetes Gestacional/prevenção & controle , Endométrio/fisiopatologia , Feminino , Estilo de Vida Saudável , Humanos , Fenômenos Fisiológicos da Nutrição Materna , Estado Nutricional , Obesidade Materna/epidemiologia , Obesidade Materna/metabolismo , Obesidade Materna/fisiopatologia , Obesidade Materna/prevenção & controle , Placenta/fisiopatologia , Gravidez , Resultado da Gravidez , Medição de Risco , Fatores de RiscoRESUMO
After undergoing remodeling, uterine spiral arteries turn into wide, flexible tubes, with low resistance. If remodeling does not occur, spontaneous abortions, intrauterine growth restriction, and pregnancy-related hypertensive disorders can ensue. Arterial transformation begins at a very early gestational stage; however, second quarter pregnancy histopathological samples have yet to pinpoint the exact moment when abnormal remodeling transpires. We examined 100 samples, taken from consecutive abortions at 12-23 gestational weeks. Following Pijnenborg and Smith guidelines, blinded pathologists analyzed clinical data on remodeling stages. Lab results showed that arterial remodeling is not synchronic in all vessels; a single sample can include various remodeling stages; neither is remodeling homogenous in a single vessel: change may be occurring in one part of the vessel, but not in another. To our knowledge, no one has published this finding. In the examined age group, Smith stage IV predominates; around week 14, substantial muscle and endothelium loss takes place. After week 17, endovascular or fibrin trophoblast does not usually occur. Although scant consensus exists on what defines preeclampsia etiology, it is clear that it involves abnormal remodeling in decidua vessels. Improved understanding requires further knowledge on both the physiological and pathological aspects of the remodeling process. We observed that muscle and endothelial tissues disappear from weeks 14-17, after which time reendothelization predominates. We list the expected proportion of spiral artery changes for each gestational age which, to date, has not been available.