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
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
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.
Assuntos
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.
Assuntos
Endotélio Vascular/patologia , Hipercolesterolemia/complicações , Microvasos/patologia , Placenta/patologia , Doenças Vasculares/etiologia , Adulto , Arginase/metabolismo , Arginina/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Endotélio Vascular/metabolismo , Feminino , Humanos , Hipercolesterolemia/fisiopatologia , Microvasos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Placenta/metabolismo , Gravidez , Doenças Vasculares/metabolismo , Doenças Vasculares/patologiaRESUMO
Insulin resistance is characteristic of pregnancies where the mother shows metabolic alterations, such as preeclampsia (PE) and gestational diabetes mellitus (GDM), or abnormal maternal conditions such as pregestational maternal obesity (PGMO). Insulin signalling includes activation of insulin receptor substrates 1 and 2 (IRS1/2) as well as Src homology 2 domain-containing transforming protein 1, leading to activation of 44 and 42 kDa mitogen-activated protein kinases and protein kinase B/Akt (Akt) signalling cascades in the human foetoplacental vasculature. PE, GDM, and PGMO are abnormal conditions coursing with reduced insulin signalling, but the possibility of the involvement of similar cell signalling mechanisms is not addressed. This review aimed to determine whether reduced insulin signalling in PE, GDM, and PGMO shares a common mechanism in the human foetoplacental vasculature. Insulin resistance in these pathological conditions results from reduced Akt activation mainly due to inhibition of IRS1/2, likely due to the increased activity of the mammalian target of rapamycin (mTOR) resulting from lower activity of adenosine monophosphate kinase. Thus, a defective signalling via Akt/mTOR in response to insulin is a central and common mechanism of insulin resistance in these diseases of pregnancy. In this review, we summarise the cell signalling mechanisms behind the insulin resistance state in PE, GDM, and PGMO focused in the Akt/mTOR signalling pathway in the human foetoplacental endothelium.
Assuntos
Diabetes Gestacional/metabolismo , Resistência à Insulina/fisiologia , Pré-Eclâmpsia/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Feminino , Humanos , Gravidez , Transdução de Sinais/fisiologiaRESUMO
Preeclampsia (PE), gestational diabetes mellitus (GDM), and maternal supraphysiological hypercholesterolaemia (MSPH) are pregnancy-related conditions that cause metabolic disruptions leading to alterations of the mother, fetus and neonate health. These syndromes result in fetoplacental vascular dysfunction, where nitric oxide (NO) plays a crucial role. PE characterizes by abnormal increase in the placental blood pressure and a negative correlation between NO level and fetal weight, suggesting that increased NO level and oxidative stress could be involved. GDM courses with macrosomia along with altered function of the fetal cardiovascular system and fetoplacental vasculature. Even when NO synthesis in the fetoplacental vasculature is increased, NO bioavailability is reduced due to the higher oxidative stress seen in this disease. In MSPH, there is an early development of atherosclerotic lesions in fetal and newborn arteries, altered function of the fetoplacental vasculature, and higher markers of oxidative stress in fetal blood and placenta, thus, vascular alterations related with NO metabolism occur as a consequence of this syndrome. Potential mechanisms of altered NO synthesis and bioavailability result from transcriptional and post-translational NO synthases (NOS) modulation, including phosphorylation/dephosphorylation cycles, coupling/uncoupling of NOS, tetrahydrobiopterin bioavailability, calcium/calmodulin-NOS and caveolin-1-NOS interaction. Additionally, oxidative stress also plays a role in the reduced NO bioavailability. This review summarizes the available information regarding lower NO bioavailability in these pregnancy pathologies. A common NO-dependent mechanism in PE, GDM and MSPH contributing to fetoplacental endothelial dysfunction is described.
Assuntos
Endotélio Vascular/metabolismo , Óxido Nítrico/metabolismo , Complicações na Gravidez/metabolismo , Doenças Vasculares/metabolismo , Animais , Feminino , Humanos , Estresse Oxidativo/fisiologia , Placenta/metabolismo , GravidezRESUMO
The alpha2-adrenergic receptor agonist Dexmedetomidine (Dex) is a sedative medication used by anesthesiologists. Dex protects the heart against ischemia-reperfusion (IR) and can also act as a preconditioning mimetic. The mechanisms involved in Dex-dependent cardiac preconditioning, and whether this action occurs directly or indirectly on cardiomyocytes, still remain unclear. The endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathway and endothelial cells are known to play key roles in cardioprotection against IR injury. Therefore, the aims of this work were to evaluate whether the eNOS/NO pathway mediates the pharmacological cardiac effect of Dex, and whether endothelial cells are required in this cardioprotective action. Isolated adult rat hearts were treated with Dex (10nM) for 25min and the dimerization of eNOS and production of NO were measured. Hearts were then subjected to global IR (30/120min) and the role of the eNOS/NO pathway was evaluated. Dex promoted the activation of eNOS and production of NO. Dex reduced the infarct size and improved the left ventricle function recovery, but this effect was reversed when Dex was co-administered with inhibitors of the eNOS/NO/PKG pathway. In addition, Dex was unable to reduce cell death in isolated adult rat cardiomyocytes subjected to simulated IR. Cardiomyocyte death was attenuated by co-culturing them with endothelial cells pre-treated with Dex. In summary, our results show that Dex triggers cardiac protection by activating the eNOS/NO signaling pathway. This pharmacological effect of Dex requires its interaction with the endothelium.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Cardiotônicos/farmacologia , Dexmedetomidina/farmacologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Cardiotônicos/uso terapêutico , Células Cultivadas , Técnicas de Cocultura , Dexmedetomidina/uso terapêutico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Maternal physiological hypercholesterolemia occurs during pregnancy, ensuring normal fetal development. In some cases, the maternal plasma cholesterol level increases to above this physiological range, leading to maternal supraphysiological hypercholesterolemia (MSPH). This condition results in endothelial dysfunction and atherosclerosis in the fetal and placental vasculature. The fetal and placental endothelial dysfunction is related to alterations in the L-arginine/nitric oxide (NO) pathway and the arginase/urea pathway and results in reduced NO production. The level of tetrahydrobiopterin (BH4), a cofactor for endothelial NO synthase (eNOS), is reduced in nonpregnant women who have hypercholesterolemia, which favors the generation of the superoxide anion rather than NO (from eNOS), causing endothelial dysfunction. However, it is unknown whether MSPH is associated with changes in the level or metabolism of BH4; as a result, eNOS function is not well understood. This review summarizes the available information on the potential link between MSPH and BH4 in causing human fetoplacental vascular endothelial dysfunction, which may be crucial for understanding the deleterious effects of MSPH on fetal growth and development.
Assuntos
Biopterinas/análogos & derivados , Endotélio Vascular/metabolismo , Hipercolesterolemia/patologia , Animais , Arginina/metabolismo , Biopterinas/metabolismo , Boroidretos/metabolismo , Colesterol/sangue , Feminino , Humanos , Hipercolesterolemia/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , GravidezRESUMO
Microvascular and macrovascular endothelial function maintains vascular reactivity. Several diseases alter endothelial function, including hypertension, obesity, and diabetes mellitus. In addition, micro- and macrovascular endothelial dysfunction is documented in GDM with serious consequences for the growing fetus. Increased l-arginine uptake via hCAT-1 and NO synthesis by eNOS is associated with GDM. These alterations are paralleled by activation of purinergic receptors and increased umbilical vein, but not arteries blood adenosine accumulation. GDM associates with NO-reduced adenosine uptake in placental endothelium, suggested to maintain and/or facilitate insulin vasodilation likely increasing hCAT-1 and eNOS expression and activity. It is proposed that increased umbilical vein blood adenosine concentration in GDM reflects a defective metabolic state of human placenta. In addition, insulin recovers GDM-alterations in hCAT-1 and eNOS in human micro- and macrovascular endothelium, and its biological actions depend on preferential activation of insulin receptors A and B restoring a normal-like from a GDM-like phenotype. We summarized existing evidence for a potential role of insulin/adenosine/micro- and macrovascular endothelial dysfunction in GDM. These mechanisms could be crucial for a better management of the mother, fetus and newborn in GDM pregnancies.