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Bradyrhizobium diazoefficiens can live inside soybean root nodules and in free-living conditions. In both states, when oxygen levels decrease, cells adjust their protein pools by gene transcription modulation. PhaR is a transcription factor involved in polyhydroxyalkanoate (PHA) metabolism but also plays a role in the microaerobic network of this bacterium. To deeply uncover the function of PhaR, we applied a multipronged approach, including the expression profile of a phaR mutant at the transcriptional and protein levels under microaerobic conditions, and the identification of direct targets and of proteins associated with PHA granules. Our results confirmed a pleiotropic function of PhaR, affecting several phenotypes, in addition to PHA cycle control. These include growth deficiency, regulation of carbon and nitrogen allocation, and bacterial motility. Interestingly, PhaR may also modulate the microoxic-responsive regulatory network by activating the expression of fixK2 and repressing nifA, both encoding two transcription factors relevant for microaerobic regulation. At the molecular level, two PhaR-binding motifs were predicted and direct control mediated by PhaR determined by protein-interaction assays revealed seven new direct targets for PhaR. Finally, among the proteins associated with PHA granules, we found PhaR, phasins, and other proteins, confirming a dual function of PhaR in microoxia.
Assuntos
Bradyrhizobium , Poli-Hidroxialcanoatos , Proteínas de Bactérias/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Bradyrhizobium/genética , Bradyrhizobium/metabolismo , Poli-Hidroxialcanoatos/metabolismo , Regulação Bacteriana da Expressão GênicaRESUMO
BACKGROUND: Maternal physiological hypercholesterolemia (MPH) occurs in pregnancy for a proper fetal development. When cholesterol increases over the physiological range, maternal supraphysiological hypercholesterolemia (MSPH) is described, a condition underdiagnosed by a lack of evidence showing its biological and clinical relevance. AIM: To determine if MSPH associates with maternal vascular dysfunction, along with changes in the composition and function of maternal HDL leading to increased cardiovascular risk. METHODS: This study included 57 women at term of pregnancy in which a lipid profile was determined. RESULTS: Maternal total cholesterol (TC) and LDL but not HDL were increased in MSPH women. The isolated HDL from a subgroup of MSPH women had a lower protein abundance and a reduced activity of the antioxidant enzyme PON1; however, an increased antioxidant capacity compared to MPH was observed, along with higher serum levels of α-tocopherol. Moreover, HDL from a subgroup of MSPH women had a lower capacity to induce NO synthesis in endothelial cells compared to MPH. In the circulation, we observed a reduced total antioxidant capacity and augmented levels of soluble VCAM, ApoB, ApoCII, ApoCIII, IL-10, and IL-12p70, as well as the cardiovascular risk ratio ApoB/ApoAI, compared to MPH women. CONCLUSION: MSPH women present dysfunctional HDL and increased atherogenic cardiovascular risk factors.
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Maternal physiological hypercholesterolemia MPH, maternal total cholesterol (TC) levels at term of pregnancy ≤280 mg/dL) occurs to assure fetal development. Maternal supraphysiological hypercholesterolemia (MSPH, TC levels >280 mg/dL) is a pathological condition associated with maternal, placental, and fetal endothelial dysfunction and early neonatal atherosclerosis development. Small extracellular vesicles (sEVs) are delivered to the extracellular space by different cells, where they modulate cell functions by transporting active signaling molecules, including proteins and miRNA. AIM: To determine whether sEVs from MSPH women could alter the function of endothelial cells (angiogenesis, endothelial activation and nitric oxide synthesis capacity). METHODS: This study included 24 Chilean women (12 MPH and 12 MSPH). sEVs were isolated from maternal plasma and characterized by sEV markers (CD9, Alix and HSP70), nanoparticle tracking analysis, transmission electron microscopy, and protein and cholesterol content. The endothelial cell line HMEC-1 was used to determine the uptake of labeled sEVs and the effects of sEVs on cell viability, endothelial tube formation, endothelial cell activation, and endothelial nitric oxide expression and function. RESULTS: In MSPH women, the plasma concentration of sEVs was increased compared to that in MPH women. MSPH-sEVs were highly taken up by HMEC-1 cells and reduced angiogenic capacity and the expression and activity of eNOS without changing cell viability or endothelial activation compared to MPH-sEVs. CONCLUSION: sEVs from MSPH women impair angiogenesis and nitric oxide synthesis in endothelial cells, which could contribute to MSPH-associated endothelial dysfunction.
Assuntos
Vesículas Extracelulares , Hipercolesterolemia , Recém-Nascido , Feminino , Humanos , Gravidez , Hipercolesterolemia/metabolismo , Células Endoteliais/metabolismo , Gestantes , Placenta/metabolismo , Óxido Nítrico/metabolismo , Colesterol/metabolismo , Vesículas Extracelulares/metabolismoRESUMO
Maternal obesity and the imbalance in linoleic acid (C18:2 n-6, LA) and alpha-linolenic acid (C18:3 n-3, ALA) levels are related with hepatic disturbances in the offspring. However, whether these alterations are present during fetal life is not well understood. Obese and normal weight pregnant women were recruited to determine fatty acids (FAs) consumption, FAs profile (in maternal erythrocytes, placenta and neonatal very low-density lipoproteins VLDL) and biomarkers of fetal liver function, such as gamma-glutamyl transferase (GGT), alpha-fetoprotein (AFP) and albumin, in umbilical cord blood. Stearic acid (C18:0, ST) was lower, and total n-3 FAs tended to be lower in umbilical cord VLDLs of obese women compared to controls. Independently of maternal obesity, GGT levels in umbilical cord blood was positively correlated with the LA content and negatively correlated with the ALA content in maternal erythrocytes. We conclude that maternal obesity and its imbalance of LA and ALA are associated with changes in biomarkers of fetal liver function.
Assuntos
Obesidade Materna , Recém-Nascido , Humanos , Feminino , Gravidez , Ácido alfa-Linolênico , Ácidos Graxos , Ácidos Graxos Essenciais , Obesidade , Ácido Linoleico , Sangue Fetal , Fígado , BiomarcadoresRESUMO
During pregnancy, the developing foetus requires large amounts of cholesterol from the maternal plasma, which is mediated by proteins such as the receptor for low-density lipoproteins (LDLR). The quantity of LDLR available in the syncytiotrophoblast plasma membrane is an important factor for the uptake, metabolism, and transfer of cholesterol to foetal circulation. Because of the relevance of this receptor for cellular and systemic cholesterol metabolism in non-placental cells, the study of mechanisms associated with LDLR trafficking, such as the availability in the cell membrane, endocytosis, recycling, sorting, and degradation, have been extensively studied. Multiple protein groups are required for proper LDL/LDLR trafficking. Changes in the function of these proteins are related to hypercholesterolemia, the main risk factor associated with cardiovascular disease. It is well known that the placenta plays an essential role as a barrier between maternal lipids and the foetus and that imbalances in maternal cholesterol levels during pregnancy are frequent and associated with cardiovascular disease in the offspring. However, there is little information regarding lipoprotein trafficking in this system. In this review, we summarize the available information on LDLR trafficking, emphasizing the few reports related to receptor biology in placental cells from normal and pathological pregnancies. We conclude that extensive research on the cell biology of the placenta is required to unravel the endocytic trafficking of proteins such as LDLR in a highly specialized cell such as the syncytiotrophoblast.
Assuntos
Doenças Cardiovasculares , Hipercolesterolemia , Doenças Cardiovasculares/metabolismo , Colesterol/metabolismo , Feminino , Humanos , Lipoproteínas LDL , Gravidez , Receptores de LDL/metabolismo , Trofoblastos/metabolismoRESUMO
INTRODUCTION: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised is a basic tool for the evaluation of people with this disease. In our country, versions are used without the necessary methodological process to adapt them culturally and to be able to certify the plausibility of the data collected. It was our goal to generate an appropriate version adapted to Argentine Spanish. METHODS: Cross-cultural adaptation of the scale was carried out, producing its Argentine version. Said production was carried out according to internationally accepted methodological procedures: sequential process of translation / synthesis / back-translation and consolidation of the version obtained by a multidisciplinary committee that solved of disagreements under Delphi methodology. The version obtained was tested on ALS people to determine of the existing syntactic - pragmatic level of difficulty, after which the final version was constituted. Difficulty level analysis was performed according to indicators: mode, median, qualitative variation index, variation ratio, accumulated frequency of positive evaluations, identification / modification of observed items (determining criterion: concordance criterion = 80%). RESULTS: After 3 rounds of consultation, the version agreed upon by the committee was obtained, obtaining agreement levels of 83.33%-100%. Its testing involved 21 functional alphabets, natives/residents, 67% men, mean age 51 years old, mean evolution 1.4 years. The general indicators supported the understanding of the version and the absence of conflicting items. DISCUSSION: The version obtained demonstrated its conceptual content validity regarding the English version, presenting not semantic nor pragmatic conflicts affecting their use in an Argentine population of ALS patients.
Introducción: La Escala Revisada de Valoración Funcional de la Esclerosis Lateral Amiotrófica es una herramienta básica para la evaluación de personas con esta enfermedad. En nuestro país se utilizan versiones sin el proceso metodológico necesario para adaptarlas culturalmente y poder certificar lo verosímil de los datos recogidos. Fue nuestro objetivo generar una apropiada versión adaptada al español argentino. Métodos: Se realizó la adaptación transcultural de la escala produciendo su versión argentina, conforme procedimientos y medidas de verificación de calidad metodológica internacionalmente aceptadas: proceso secuencial de traducción/síntesis/retrotraducción; resolución de discrepancias y consolidación de la versión obtenida por comité multidisciplinario bajo metodología Delphi; puesta a prueba de dicha versión en una población de personas con esclerosis lateral amiotrófica analizando el nivel de dificultad sintáctico-pragmático; constitución de la versión final. El análisis del nivel de dificultad se constituyó en base a los siguientes indicadores: moda, mediana, índice variación cualitativa, razón de variación, frecuencia acumulada de apreciaciones positivas, identificación / modificación de ítems observados, tomando como base un criterio de concordancia = 80%. Resultados: Tras 3 rondas de consulta se obtuvo la versión consensuada por el comité, obteniéndose niveles de concordancia del 83,33%-100%. Su puesta a prueba involucró a 21 alfabetos funcionales, nativos/residentes, 67% hombres, media edad 51 años, media evolución 1,4 años. Ausencia de dificultad a nivel comprensión y la ausencia de ítems conflictivos. Discusión: La versión obtenida demostró su validez de contenido conceptual respecto de la original, sin presentar conflictos semánticos o pragmáticos que afecten su uso en nuestra población.
Assuntos
Esclerose Lateral Amiotrófica , Comparação Transcultural , Esclerose Lateral Amiotrófica/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Inquéritos e Questionários , TraduçõesRESUMO
Maternal physiological hypercholesterolemia (MPH) occurs during pregnancy to assure fetal development. Some pregnant women develop maternal supraphysiological hypercholesterolemia (MSPH) characterized by increased levels of low-density lipoprotein (LDL). We aim to determine if proprotein convertase subtilisin/kexin type 9 (PCSK9) levels (a protein that regulate the availability of LDL receptor in the cells surface), as well as the composition and function of LDL, are modulated in MSPH women. This study included 122 pregnant women. Maternal total cholesterol (TC), LDL, triglycerides and PCSK9 increased from first (T1) to third trimester (T3) in MPH women. At T3, maternal TC, LDL, PCSK9 and placental abundances of PCSK9 were significantly higher in MPSH compared to MPH. Circulating PCSK9 levels were correlated with LDL at T3. In MSPH women, the levels of lipid peroxidation and oxidized LDL were significantly higher compared to MPH. LDL isolated from MSPH women presented significantly higher triglycerides and ApoB but lower levels of ApoAI compared to MPH. The formation of conjugated dienes was earlier in LDL from MSPH and in endothelial cells incubated with these LDLs; the levels of reactive oxygen species were significantly higher compared to LDL from MPH. We conclude that increased maternal PCSK9 would contribute to the maternal elevated levels of pro-atherogenic LDL in MSPH, which could eventually be related to maternal vascular dysfunction.
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Resumen Introducción: La Escala Revisada de Valoración Funcional de la Esclerosis Lateral Amiotrófica es una herramienta básica para la evaluación de personas con esta enfermedad. En nuestro país se utilizan versiones sin el proceso metodológico necesario para adaptarlas culturalmente y poder certificar lo vero símil de los datos recogidos. Fue nuestro objetivo generar una apropiada versión adaptada al español argentino. Métodos: Se realizó la adaptación transcultural de la escala produciendo su versión argentina, conforme proce dimientos y medidas de verificación de calidad metodológica internacionalmente aceptadas: proceso secuencial de traducción/síntesis/retrotraducción; resolución de discrepancias y consolidación de la versión obtenida por comité multidisciplinario bajo metodología Delphi; puesta a prueba de dicha versión en una población de perso nas con esclerosis lateral amiotrófica analizando el nivel de dificultad sintáctico-pragmático; constitución de la versión final. El análisis del nivel de dificultad se constituyó en base a los siguientes indicadores: moda, mediana, índice variación cualitativa, razón de variación, frecuencia acumulada de apreciaciones positivas, identificación/ modificación de ítems observados, tomando como base un criterio de concordancia ≥ 80%. Resultados: Tras 3 rondas de consulta se obtuvo la versión consensuada por el comité, obteniéndose niveles de concordancia del 83,33%-100%. Su puesta a prueba involucró a 21 alfabetos funcionales, nativos/residentes, 67% hombres, media edad 51 años, media evolución 1,4 años. Ausencia de dificultad a nivel comprensión y la ausencia de ítems conflictivos. Discusión: La versión obtenida demostró su validez de contenido conceptual respecto de la original, sin presentar conflictos semánticos o pragmáticos que afecten su uso en nuestra población.
Abstract Introduction: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised is a basic tool for the evaluation of people with this disease. In our country, versions are used without the necessary methodological process to adapt them culturally and to be able to certify the plausibility of the data collected. It was our goal to generate an appropriate version adapted to Argentine Spanish. Methods: Cross-cultural adaptation of the scale was ca rried out, producing its Argentine version. Said production was carried out according to internationally accepted methodological procedures: sequential process of translation / synthesis / back-translation and consolidation of the version obtained by a multidisciplinary committee that solved of disagreements under Delphi methodology. The version obtained was tested on ALS people to determine of the existing syntactic - pragmatic level of difficulty, after which the final version was constituted. Difficulty level analysis was performed according to indicators: mode, median, qualitative variation index, variation ratio, accumulated frequency of positive evaluations, identification/ modification of observed items (determining criterion: concordance criterion ≥ 80%). Results: After 3 rounds of consultation, the version agreed upon by the committee was obtained, obtaining agreement levels of 83.33%-100%. Its testing involved 21 functional alphabets, natives/residents, 67% men, mean age 51 years old, mean evolution 1.4 years. The general indicators supported the understanding of the version and the absence of conflicting items. Discussion: The version obtained demonstrated its conceptual content validity regarding the English version, presenting not semantic nor pragmatic conflicts affecting their use in an Argentine population of ALS patients.
RESUMO
The placenta participates in cholesterol biosynthesis and metabolism and regulates exchange between the maternal and fetal compartments. The fetus has high cholesterol requirements, and it is taken up and synthesized at elevated rates during pregnancy. In placental cells, the major source of cholesterol is the internalization of lipoprotein particles from maternal circulation by mechanisms that are not fully understood. As in hepatocytes, syncytiotrophoblast uptake of lipoprotein cholesterol involves lipoprotein receptors such as low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI). Efflux outside the cells requires proteins such as the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. However, mechanisms associated with intracellular traffic of cholesterol in syncytiotrophoblasts are mostly unknown. In hepatocytes, uptaken cholesterol is transported to acidic late endosomes (LE) and lysosomes (LY). Proteins such as Niemann-Pick type C 1 (NPC1), NPC2, and StAR related lipid transfer domain containing 3 (STARD3) are required for cholesterol exit from the LE/LY. These proteins transfer cholesterol from the lumen of the LE/LY into the LE/LY-limiting membrane and then export it to the endoplasmic reticulum, mitochondria, or plasma membrane. Although the production, metabolism, and transport of cholesterol in placental cells are well explored, there is little information on the role of proteins related to intracellular cholesterol traffic in placental cells during physiological or pathological pregnancies. Such studies would be relevant for understanding fetal and placental cholesterol management. Oxidative stress, induced by generating excess reactive oxygen species (ROS), plays a critical role in regulating various cellular and biological functions and has emerged as a critical common mechanism after lysosomal and mitochondrial dysfunction. This review discusses the role of cholesterol, lysosomal and mitochondrial dysfunction, and ROS in the development and progression of hypercholesterolemic pregnancies.
Assuntos
Doenças Cardiovasculares , Diabetes Gestacional , Doenças Fetais , Hipercolesterolemia , Gravidez , Feminino , Humanos , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Epigênese GenéticaRESUMO
BACKGROUND: During pregnancy, the renin-angiotensin-aldosterone system (RAAS) undergoes major changes to preserve normal blood pressure (BP) and placental blood flow and to ensure a good pregnancy outcome. Abnormal aldosterone-renin metabolism is a risk factor for arterial hypertension and cardiovascular risk, but its association with pathological conditions in pregnancy remains unknown. Moreover, potential biomarkers associated with these pathological conditions should be identified. AIM: To study a cohort of normotensive pregnant women according to their serum aldosterone and plasma renin levels and assay their small extracellular vesicles (sEVs) and a specific protein cargo (LCN2, AT1R). METHODS: A cohort of 54 normotensive pregnant women at term gestation was included. We determined the BP, serum aldosterone, and plasma renin concentrations. In a subgroup, we isolated their plasma sEVs and semiquantitated two EV proteins (AT1R and LCN2). RESULTS: We set a normal range of aldosterone and renin based on the interquartile range. We identified 5/54 (9%) pregnant women with elevated aldosterone and low renin levels and 5/54 (9%) other pregnant women with low aldosterone and elevated renin levels. No differences were found in sEV-LCN2 or sEV-AT1R. CONCLUSION: We found that 18% of normotensive pregnant women had either high aldosterone or high renin levels, suggesting a subclinical status similar to primary aldosteronism or hyperreninemia, respectively. Both could evolve to pathological conditions by affecting the maternal vascular and renal physiology and further the BP. sEVs and their specific cargo should be further studied to clarify their role as potential biomarkers of RAAS alterations in pregnant women.
Assuntos
Hipertensão , Renina , Aldosterona , Pressão Sanguínea , Feminino , Humanos , Placenta/metabolismo , Gravidez , Resultado da Gravidez , Gestantes , Sistema Renina-Angiotensina/fisiologiaRESUMO
Early human placental development begins with blastocyst implantation, then the trophoblast differentiates and originates the cells required for a proper fetal nutrition and placental implantation. Among them, extravillous trophoblast corresponds to a non-proliferating trophoblast highly invasive that allows the vascular remodeling which is essential for appropriate placental perfusion and to maintain the adequate fetal growth. This process involves different placental cell types as well as molecules that allow cell growth, cellular adhesion, tissular remodeling, and immune tolerance. Remarkably, some of the cellular processes required for proper placentation are common between placental and cancer cells to finally support tumor growth. Indeed, as in placentation trophoblasts invade and migrate, cancer cells invade and migrate to promote tumor metastasis. However, while these processes respond to a controlled program in trophoblasts, in cancer cells this regulation is lost. Interestingly, it has been shown that autophagy, a process responsible for the degradation of damaged proteins and organelles to maintain cellular homeostasis, is required for invasion of trophoblast cells and for vascular remodeling during placentation. In cancer cells, autophagy has a dual role, as it has been shown both as tumor promoter and inhibitor, depending on the stage and tumor considered. In this review, we summarized the similarities and differences between trophoblast cell invasion and cancer cell metastasis specifically evaluating the role of autophagy in both processes.
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Cardiovascular diseases (CVD) remain a major cause of death worldwide. Evidence suggests that the risk for CVD can increase at the fetal stages due to maternal metabolic diseases, such as gestational diabetes mellitus (GDM) and maternal supraphysiological hypercholesterolemia (MSPH). GDM is a hyperglycemic, inflammatory, and insulin-resistant state that increases plasma levels of free fatty acids and triglycerides, impairs endothelial vascular tone regulation, and due to the increased nutrient transport, exposes the fetus to the altered metabolic conditions of the mother. MSPH involves increased levels of cholesterol (mainly as low-density lipoprotein cholesterol) which also causes endothelial dysfunction and alters nutrient transport to the fetus. Despite that an association has already been established between MSPH and increased CVD risk, however, little is known about the cellular processes underlying this relationship. Our knowledge is further obscured when the simultaneous presentation of MSPH and GDM takes place. In this context, GDM and MSPH may substantially increase fetal CVD risk due to synergistic impairment of placental nutrient transport and endothelial dysfunction. More studies on the separate and/or cumulative role of both processes are warranted to suggest specific treatment options.
Assuntos
Doenças Cardiovasculares , Diabetes Gestacional , Doenças Fetais , Hipercolesterolemia , Doenças Cardiovasculares/epidemiologia , Diabetes Gestacional/epidemiologia , Feminino , Doenças Fetais/epidemiologia , Humanos , Hipercolesterolemia/epidemiologia , Gravidez , Medição de RiscoRESUMO
Hypercholesterolemia is one of the main risk factors associated with atherosclerosis and cardiovascular disease, the leading cause of death worldwide. During pregnancy, maternal hypercholesterolemia develops, and it can occur in a physiological (MPH) or supraphysiological (MSPH) manner, where MSPH is associated with endothelial dysfunction and early atherosclerotic lesions in the fetoplacental vasculature. In the pathogenesis of atherosclerosis, endothelial activation and endothelial dysfunction, characterized by an imbalance in the bioavailability of nitric oxide, contribute to the early stages of this disease. Macrophages conversion to foam cells, cholesterol efflux from these cells and its differentiation into a pro- or anti-inflammatory phenotype are also important processes that contribute to atherosclerosis. In adults it has been reported that native and modified HDL and LDL play an important role in endothelial and macrophage function. In this review it is proposed that fetal lipoproteins could be also relevant factors involved in the detrimental vascular effects described in MSPH. Changes in the composition and function of neonatal lipoproteins compared to adults has been reported and, although in MSPH pregnancies the fetal lipid profile does not differ from MPH, differences in the lipidomic profiles of umbilical venous blood have been reported, which could have implications in the vascular function. In this review we summarize the available information regarding the effects of lipoproteins on endothelial and macrophage function, emphasizing its possible implications on fetal adverse outcomes associated to maternal hypercholesterolemia during pregnancy.
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Células Endoteliais/metabolismo , Hipercolesterolemia/metabolismo , Lipoproteínas/metabolismo , Macrófagos/metabolismo , Complicações na Gravidez/metabolismo , Feminino , Humanos , Gravidez , Resultado da GravidezRESUMO
Gestational Diabetes Mellitus (GDM) is characterized by abnormal maternal D-glucose metabolism and altered insulin signaling. Dysregulation of thyroid hormones (TH) tri-iodethyronine (T3) and L-thyroxine (T4) Hormones had been associated with GDM, but the physiopathological meaning of these alterations is still unclear. Maternal TH cross the placenta through TH Transporters and their Deiodinases metabolize them to regulate fetal TH levels. Currently, the metabolism of TH in placentas with GDM is unknown, and there are no other studies that evaluate the fetal TH from pregnancies with GDM. Therefore, we evaluated the levels of maternal TH during pregnancy, and fetal TH at delivery, and the expression and activity of placental deiodinases from GDM pregnancies. Pregnant women were followed through pregnancy until delivery. We collected blood samples during 10-14, 24-28, and 36-40 weeks of gestation for measure Thyroid-stimulating hormone (TSH), Free T4 (FT4), Total T4 (TT4), and Total T3 (TT3) concentrations from Normal Glucose Tolerance (NGT) and GDM mothers. Moreover, we measure fetal TSH, FT4, TT4, and TT3 in total blood cord at the delivery. Also, we measured the placental expression of Deiodinases by RT-PCR, western-blotting, and immunohistochemistry. The activity of Deiodinases was estimated quantified rT3 and T3 using T4 as a substrate. Mothers with GDM showed higher levels of TT3 during all pregnancy, and an increased in TSH during second and third trimester, while lower concentrations of neonatal TT4, FT4, and TT3; and an increased TSH level in umbilical cord blood from GDM. Placentae from GDM mothers have a higher expression and activity of Deiodinase 3, but lower Deiodinase 2, than NGT mothers. In conclusion, GDM favors high levels of TT3 during all gestation in the mother, low levels in TT4, FT4 and TT3 at the delivery in neonates, and increases deiodinase 3, but reduce deiodinase 2 expression and activity in the placenta.
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Diabetes Gestacional/sangue , Regulação Enzimológica da Expressão Gênica , Iodeto Peroxidase/biossíntese , Placenta/metabolismo , Tiroxina/sangue , Tri-Iodotironina/sangue , Adulto , Diabetes Gestacional/patologia , Feminino , Humanos , Placenta/patologia , Gravidez , Iodotironina Desiodinase Tipo IIRESUMO
During pregnancy, there is a progressive increase in the levels of maternal cholesterol, a lipid that is essential for foetal growth and development. This increase can occur in a physiological (MPH) or supraphysiological (MSPH) manner, where MSPH is associated with detrimental effects on the mother and foetus, including endothelial dysfunction, oxidative stress, and atherosclerosis. Cholesterol is transported from the maternal to the foetal circulation through the placenta by a process that encompasses two main events: cholesterol uptake and efflux. The main receptors and transporters that participate in cholesterol transport are expressed in the human placenta, and their regulation in normal and pathological pregnancies has been evaluated. However, whether elevated levels of cholesterol induce these detrimental changes and whether their expression and function changes in the MSPH condition is still under study, along with the cell types involved in placental cholesterol traffic. Moreover, aside from cholesterol levels, the composition and function of lipoproteins have recently become important to study as these factors may also contribute to the atherogenic process. There is information regarding the maternal and neonatal lipoproteins profile and their changes during pregnancy. However, there are no reports that evaluate the changes of these lipoproteins in MSPH pregnancies. The latter could be relevant considering the consequences that MSPH has on the foetal vasculature. In this review, we summarize the available information regarding cholesterol transport through the placenta and the metabolism of maternal and neonatal lipoproteins in MPH and MSPH conditions, suggesting the importance of increasing our knowledge about these conditions and the monitoring of maternal cholesterol levels during pregnancy.
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Colesterol/metabolismo , Hipercolesterolemia/sangue , Recém-Nascido/sangue , Lipoproteínas/sangue , Placenta/metabolismo , Complicações na Gravidez/sangue , Transporte Biológico , Feminino , Humanos , GravidezRESUMO
Maternal physiological (MPH) or supraphysiological hypercholesterolaemia (MSPH) occurs during pregnancy. Cholesterol trafficking from maternal to foetal circulation requires the uptake of maternal LDL and HDL by syncytiotrophoblast and cholesterol efflux from this multinucleated tissue to ApoA-I and HDL. We aimed to determine the effects of MSPH on placental cholesterol trafficking. Placental tissue and primary human trophoblast (PHT) were isolated from pregnant women with total cholesterol <280 md/dL (MPH, n = 27) or ≥280 md/dL (MSPH, n = 28). The lipid profile in umbilical cord blood from MPH and MSPH neonates was similar. The abundance of LDL receptor (LDLR) and HDL receptor (SR-BI) was comparable between MSPH and MPH placentas. However, LDLR was localized mainly in the syncytiotrophoblast surface and was associated with reduced placental levels of its ligand ApoB. In PHT from MSPH, the uptake of LDL and HDL was lower compared to MPH, without changes in LDLR and reduced levels of SR-BI. Regarding cholesterol efflux, in MSPH placentas, the abundance of cholesterol transporter ABCA1 was increased, while ABCG1 and SR-BI were reduced. In PHT from MSPH, the cholesterol efflux to ApoA-I was increased and to HDL was reduced, along with reduced levels of ABCG1, compared to MPH. Inhibition of SR-BI did not change cholesterol efflux in PHT. The TC content in PHT was comparable in MPH and MSPH cells. However, free cholesterol was increased in MSPH cells. We conclude that MSPH alters the trafficking and content of cholesterol in placental trophoblasts, which could be associated with changes in the placenta-mediated maternal-to-foetal cholesterol trafficking.
Assuntos
Colesterol/metabolismo , Hipercolesterolemia/sangue , Recém-Nascido/sangue , Complicações na Gravidez/sangue , Trofoblastos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Apolipoproteína A-I/metabolismo , Transporte Biológico , Células Cultivadas , Feminino , Sangue Fetal/química , Humanos , Lipoproteínas/sangue , Troca Materno-Fetal , Pessoa de Meia-Idade , Placenta/metabolismo , Gravidez , Receptores de LDL/metabolismo , Triglicerídeos/sangue , Adulto JovemRESUMO
: Gestational diabetes mellitus (GDM) associates with fetal endothelial dysfunction (ED), which occurs independently of adequate glycemic control. Scarce information exists about the impact of different GDM therapeutic schemes on maternal dyslipidemia and obesity and their contribution to the development of fetal-ED. The aim of this study was to evaluate the effect of GDM-treatments on lipid levels in nonobese (N) and obese (O) pregnant women and the effect of maternal cholesterol levels in GDM-associated ED in the umbilical vein (UV). O-GDM women treated with diet showed decreased total cholesterol (TC) and low-density lipoproteins (LDL) levels with respect to N-GDM ones. Moreover, O-GDM women treated with diet in addition to insulin showed higher TC and LDL levels than N-GDM women. The maximum relaxation to calcitonin gene-related peptide of the UV rings was lower in the N-GDM group compared to the N one, and increased maternal levels of TC were associated with even lower dilation in the N-GDM group. We conclude that GDM-treatments modulate the TC and LDL levels depending on maternal weight. Additionally, increased TC levels worsen the GDM-associated ED of UV rings. This study suggests that it could be relevant to consider a specific GDM-treatment according to weight in order to prevent fetal-ED, as well as to consider the possible effects of maternal lipids during pregnancy.
Assuntos
Diabetes Gestacional/dietoterapia , Dislipidemias/dietoterapia , Troca Materno-Fetal/fisiologia , Obesidade/dietoterapia , Veias Umbilicais/fisiopatologia , Adulto , Peso ao Nascer/fisiologia , Glicemia/análise , Índice de Massa Corporal , Peso Corporal/fisiologia , Colesterol/sangue , Colesterol/metabolismo , Estudos Transversais , Diabetes Gestacional/sangue , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/metabolismo , Dieta com Restrição de Carboidratos , Dislipidemias/sangue , Dislipidemias/etiologia , Dislipidemias/fisiopatologia , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Recém-Nascido , Lipoproteínas LDL/sangue , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/metabolismo , Obesidade/fisiopatologia , Circulação Placentária/fisiologia , Gravidez , Estudos Retrospectivos , Adulto JovemRESUMO
Dyslipidaemia occurs in pregnancy to secure foetal development. The mother shows a physiological increase in plasma total cholesterol and Triglycerides (TG) as pregnancy progresses (i.e. maternal physiological dyslipidaemia in pregnancy). However, in some women pregnancy-associated dyslipidaemia exceeds this physiological adaptation. The consequences of this condition on the developing fetus include endothelial dysfunction of the foetoplacental vasculature and development of foetal aortic atherosclerosis. Gestational Diabetes Mellitus (GDM) associates with abnormal function of the foetoplacental vasculature due to foetal hyperglycaemia and hyperinsulinaemia, and associates with development of cardiovascular disease in adulthood. Supraphysiological dyslipidaemia is also detected in GDM pregnancies. Although there are several studies showing the alteration in the maternal and neonatal lipid profile in GDM pregnancies, there are no studies addressing the effect of dyslipidaemia in the maternal and foetal vasculature. The literature reviewed suggests that dyslipidaemia in GDM pregnancy should be an additional factor contributing to worsen GDM-associated endothelial dysfunction by altering signalling pathways involving nitric oxide bioavailability and neonatal lipoproteins.
Assuntos
Doenças da Aorta/sangue , Aterosclerose/sangue , Glicemia/metabolismo , Diabetes Gestacional/sangue , Dislipidemias/sangue , Doenças Fetais/sangue , Lipoproteínas/sangue , Circulação Placentária , Efeitos Tardios da Exposição Pré-Natal , Animais , Doenças da Aorta/diagnóstico , Doenças da Aorta/fisiopatologia , Aterosclerose/diagnóstico , Aterosclerose/fisiopatologia , Biomarcadores/sangue , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/fisiopatologia , Dislipidemias/diagnóstico , Dislipidemias/fisiopatologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/fisiopatologia , Humanos , Gravidez , Fatores de RiscoRESUMO
Maternal physiological or supraphysiological hypercholesterolemia (MPH, MSPH) occurs during pregnancy. MSPH is associated with foetal endothelial dysfunction and atherosclerosis. However, the potential effects of MSPH on placental microvasculature are unknown. The aim of this study was to determine whether MSPH alters endothelial function in the placental microvasculature both ex vivo in venules and arterioles from the placental villi and in vitro in primary cultures of placental microvascular endothelial cells (hPMEC). Total cholesterol < 280 mg/dL indicated MPH, and total cholesterol ≥280 mg/dL indicated MSPH. The maximal relaxation to histamine, calcitonin gene-related peptide and adenosine was reduced in MSPH venule and arteriole rings. In hPMEC from MSPH placentas, nitric oxide synthase (NOS) activity and L-arginine transport were reduced without changes in arginase activity or the protein levels of endothelial NOS (eNOS), human cationic amino acid 1 (hCAT-1), hCAT-2A/B or arginase II compared with hPMEC from MPH placentas. In addition, it was shown that adenosine acts as a vasodilator of the placental microvasculature and that NOS is active in hPMEC. We conclude that MSPH alters placental microvascular endothelial function via a NOS/L-arginine imbalance. This work also reinforces the concept that placental endothelial cells from the macro- and microvasculature respond differentially to the same pathological condition.