Avaliação do envolvimento do óxido nítrico nos efeitos materno-fetais da pravastatina na hipertensão gestacional em ratas
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Data
2018-12-04
Autores
Chimini, Jessica Sabbatine
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Universidade Estadual Paulista (Unesp)
Resumo
Durante a gestação, diversas adaptações fisiológicas ocorrem no organismo materno para atender as necessidades nutricionais do feto em desenvolvimento. Entre essas adaptações, encontramos aumento do débito cardíaco e do volume sanguíneo, os quais são compensados pela drástica redução da resistência vascular sistêmica, promovendo a manutenção da pressão arterial materna nas gestações. O endotélio vascular apresenta um importante papel neste processo fisiológico por secretar fatores vasoativos como o óxido nítrico, um vasodilatador que se encontra aumentado em gestações saudáveis. Em algumas mulheres, falhas nesses mecanismos podem causar desordens hipertensivas gestacionais. A pré-eclâmpsia é uma desordem hipertensiva gestacional caracterizada pela elevação da pressão arterial (≥ 140 x 90 mmHg), após a 20ª semana gestacional. É frequentemente acompanhada de proteinúria e acomete 5-8% das gestantes. Atualmente, embora a fisiopatologia da pré-eclâmpsia seja desconhecida, estudos sugerem que sua ocorrência envolva migração deficiente de citotrofoblastos, culminando em má placentação e consequente isquemia/hipóxia placentária, responsável pela liberação de fatores bioativos promovendo danos às células endoteliais. A disfunção endotelial resulta na redução da biodisponibilidade de óxido nítrico, gerando as principais características da pré-eclâmpsia, como hipertensão materna e restrição de crescimento fetal. Recentes estudos apontam a importância da manutenção dos níveis de óxido nítrico por estar associada a gestações saudáveis. As estatinas vem sendo utilizadas em doenças cardiovasculares por seus efeitos vasoprotetores que envolvem aumento da síntese de óxido nítrico. A pravastatina é a estatina que apresenta menor potencial teratogênico, por esse motivo, é empregada em estudos clínicos e experimentais durante a gestação. Esse trabalho teve o objetivo de investigar os efeitos da pravastatina na formação de óxido nítrico placentário, função vascular e endotelial, equilíbrio angiogênico, estresse oxidativo, pressão arterial materna e parâmetros feto-placentários em ratas prenhes hipertensas. Para realização dos trabalhos, ratas Wistar prenhes foram utilizadas. A hipertensão gestacional foi induzida pelo modelo DOCAsal, que consiste na administração intraperitoneal de acetato de desoxicorticosterona e substituição da água dos animais por solução salina, um modelo de imposição de aumento de volume. As ratas prenhes normotensas e hipertensas foram tratadas com pravastatina. Nós observamos que a pravastatina previne o aumento da pressão arterial e melhora os parâmetros feto-placentários em ratas submetidas ao modelo DOCA-sal. Além disso, restaura o equilíbrio angiogênico/anti-angiogênico, reduzindo níveis de sFlt-1 associado ao aumento dos níveis de PlGF, impede aumentos exacerbados de estresse oxidativo, previne a hiperreatividade ao vasoconstritor fenilefrina, previne o comprometimento da função endotelial e aumenta os níveis placentários de óxido nítrico. Todavia, nós mostramos que os níveis placentários de óxido nítrico aumentam em ratas prenhes hipertensas, assim como os níveis de PlGF e o peso placentário aumenta em ambos os grupos tratados com pravastatina. Por esse motivo, concluise que a pravastatina parece ter efeito tanto materno, atuando na prevenção do aumento da pressão arterial, quanto fetal, atuando na região uteroplacentária, melhorando o suprimento nutricional para os filhotes.
During gestation, several physiological adaptations occur in the maternal organism to provide the nutritional demands of the developing fetus. Among these adaptations, we found increase in cardiac output and blood volume, which are compensated by the drastic reduction of systemic vascular resistance, promoting the maintenance of maternal blood pressure in gestations. Vascular endothelium plays an important role in this physiological process by secreting vasoactive factors such as nitric oxide, a vasodilator that is increased in healthy pregnancies. In some women, fails in these mechanisms may cause gestational hypertensive disorders. Preeclampsia is a gestational hypertensive disorder characterized by elevated blood pressure (≥ 140 x 90 mmHg) after the 20th gestational week. It is often accompanied by proteinuria and affects 5-8% of pregnant women. Currently, although the pathophysiology of preeclampsia is unknown, studies suggest that its occurrence involves poor migration of cytotrophoblasts culminating in poor placentation and consequent ischemia/placental hypoxia, responsible for the release of bioactive factors promoting damage to endothelial cells. Endothelial dysfunction results in the reduction of the bioavailability of nitric oxide leading to the occurrence of the main characteristics of preeclampsia, mainly maternal hypertension and fetal growth restriction. Recent studies point to the importance of maintaining levels of nitric oxide, which is associated with healthy pregnancies. Statins have been used in cardiovascular diseases because of their vasoprotective effects, which involve increased nitric oxide synthesis. Pravastatin is the statin that has lower teratogenic potential, therefore, it is used in clinical and experimental studies during pregnancy. The objective of this study was to investigate the effects of pravastatin on placental nitric oxide formation, vascular and endothelial function, angiogenic balance, oxidative stress, maternal blood pressure and fetal-placental parameters in hypertensive pregnant rats. For the accomplishment of this study, pregnant Wistar rats were used. Initially, gestational hypertension was induced by the DOCA-salt model, which consist of the intraperitoneal administration of deoxycorticosterone acetate and the replacement of the water of the animals by saline solution, a model of volume increase imposition. Normotensive and hypertensive pregnant rats were treated with pravastatin. We have observed that pravastatin prevents increased blood pressure and improves fetal-placental parameters in rats submitted to the DOCA-salt model. In addition, it restores the angiogenic/anti-angiogenic balance, reducing sFlt-1 levels associated with increased PlGF levels, prevents exacerbated increases in oxidative stress, prevents hyperreactivity to a vasoconstrictor, prevents endothelial function impairment and increases in placental nitric oxide levels. However, we have shown that placental nitric oxide levels increase in hypertensive pregnant rats, as well as PlGF levels and placental weight increase in both pravastatin-treated groups. For this reason, we conclude that pravastatin seems to have an effect both maternal, acting in the prevention of increased blood pressure, and fetal, acting in the uteroplacental region, improving nutritional supply for puppies.
During gestation, several physiological adaptations occur in the maternal organism to provide the nutritional demands of the developing fetus. Among these adaptations, we found increase in cardiac output and blood volume, which are compensated by the drastic reduction of systemic vascular resistance, promoting the maintenance of maternal blood pressure in gestations. Vascular endothelium plays an important role in this physiological process by secreting vasoactive factors such as nitric oxide, a vasodilator that is increased in healthy pregnancies. In some women, fails in these mechanisms may cause gestational hypertensive disorders. Preeclampsia is a gestational hypertensive disorder characterized by elevated blood pressure (≥ 140 x 90 mmHg) after the 20th gestational week. It is often accompanied by proteinuria and affects 5-8% of pregnant women. Currently, although the pathophysiology of preeclampsia is unknown, studies suggest that its occurrence involves poor migration of cytotrophoblasts culminating in poor placentation and consequent ischemia/placental hypoxia, responsible for the release of bioactive factors promoting damage to endothelial cells. Endothelial dysfunction results in the reduction of the bioavailability of nitric oxide leading to the occurrence of the main characteristics of preeclampsia, mainly maternal hypertension and fetal growth restriction. Recent studies point to the importance of maintaining levels of nitric oxide, which is associated with healthy pregnancies. Statins have been used in cardiovascular diseases because of their vasoprotective effects, which involve increased nitric oxide synthesis. Pravastatin is the statin that has lower teratogenic potential, therefore, it is used in clinical and experimental studies during pregnancy. The objective of this study was to investigate the effects of pravastatin on placental nitric oxide formation, vascular and endothelial function, angiogenic balance, oxidative stress, maternal blood pressure and fetal-placental parameters in hypertensive pregnant rats. For the accomplishment of this study, pregnant Wistar rats were used. Initially, gestational hypertension was induced by the DOCA-salt model, which consist of the intraperitoneal administration of deoxycorticosterone acetate and the replacement of the water of the animals by saline solution, a model of volume increase imposition. Normotensive and hypertensive pregnant rats were treated with pravastatin. We have observed that pravastatin prevents increased blood pressure and improves fetal-placental parameters in rats submitted to the DOCA-salt model. In addition, it restores the angiogenic/anti-angiogenic balance, reducing sFlt-1 levels associated with increased PlGF levels, prevents exacerbated increases in oxidative stress, prevents hyperreactivity to a vasoconstrictor, prevents endothelial function impairment and increases in placental nitric oxide levels. However, we have shown that placental nitric oxide levels increase in hypertensive pregnant rats, as well as PlGF levels and placental weight increase in both pravastatin-treated groups. For this reason, we conclude that pravastatin seems to have an effect both maternal, acting in the prevention of increased blood pressure, and fetal, acting in the uteroplacental region, improving nutritional supply for puppies.
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Palavras-chave
hipertensão gestacional, óxido nítrico, ratas, pravastatina, gestational hypertension, nitric oxide, rats, pravastatin