ABSTRACT
Intrauterine growth retardation (IUGR) is associated with the development of adult-onset diseases, including pulmonary hypertension. However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular dysfunction later in life is not fully understood. Here, we investigated the role of tyrosine phosphorylation of voltage-gated potassium channel 1.5 (Kv1.5) in this prenatal event that results in exaggerated adult vascular dysfunction. A rat model of chronic hypoxia (2 weeks of hypoxia at 12 weeks old) following IUGR was used to investigate the physiological and structural effect of intrauterine malnutrition on the pulmonary artery by evaluating pulmonary artery systolic pressure and vascular diameter in male rats. Kv1.5 expression and tyrosine phosphorylation in pulmonary artery smooth muscle cells (PASMCs) were determined. We found that IUGR increased mean pulmonary artery pressure and resulted in thicker pulmonary artery smooth muscle layer in 14-week-old rats after 2 weeks of hypoxia, while no difference was observed in normoxia groups. In the PASMCs of IUGR-hypoxia rats, Kv1.5 mRNA and protein expression decreased while that of tyrosine-phosphorylated Kv1.5 significantly increased. These results demonstrate that IUGR leads to exaggerated chronic hypoxia pulmonary arterial hypertension (CH-PAH) in association with decreased Kv1.5 expression in PASMCs. This phenomenon may be mediated by increased tyrosine phosphorylation of Kv1.5 in PASMCs and it provides new insight into the prevention and treatment of IUGR-related CH-PAH.
Subject(s)
Animals , Male , Female , Pregnancy , Organophosphates/metabolism , Polymers/metabolism , Kv1.5 Potassium Channel/analysis , Fetal Hypoxia/complications , Fetal Hypoxia/physiopathology , Fetal Growth Retardation/metabolism , Hypertension, Pulmonary/etiology , Muscle, Smooth, Vascular/chemistry , Phosphorylation , Prenatal Exposure Delayed Effects/metabolism , Pulmonary Artery/physiopathology , Pulmonary Artery/pathology , Time Factors , RNA, Messenger/analysis , Immunohistochemistry , Immunoblotting , Random Allocation , Up-Regulation , Fluorescent Antibody Technique , Rats, Sprague-Dawley , Malnutrition/complications , Disease Models, Animal , Fetal Growth Retardation/etiology , Real-Time Polymerase Chain Reaction , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/pathology , Muscle, Smooth, Vascular/pathologyABSTRACT
A centralização do fluxo sanguíneo fetal é um fenômeno de compensação vascular bastante estudado na atualidade. Trata-se de alterações na resistência da circulação fetal, caracterizada pela redistribuição hemodinâmica do fluxo sanguíneo, com perfusão preferencial para órgãos nobres (cérebro, coração e glândulas adrenais) em detrimento dos pulmões, rins, baço e esqueleto, o que pode ser diagnosticado pelo estudo dopplervelocimétrico. O momento ideal para intervenção obstétrica ainda não é consenso. Uma das grandes preocupações, em relação à avaliação da vitalidade fetal, diz respeito ao momento ideal para interrupção da gravidez, uma vez que alguns dos métodos utilizados apresentam uma alta frequência de resultado falso-positivos, podendo ocasionar um nascimento prematuro, por vezes, desnecessário. Em fetos muito prematuros a opção pela interrupção da gravidez pode trazer consequências irreversíveis. Na tentativa de minimizar os danos, optou-se pela realização de uma revisão, baseada nas melhores evidências sobre a conduta nos fetos centralizados.
Fetal brain-sparing effect is a vascular compensation phenomenon widely studied today. Diagnosed by Doppler study it consists of changes on resistance in the fetal circulation characterized by hemodynamic redistribution of blood flow, with preferential perfusion to brain, heart and adrenal glands compared to the lungs, kidneys, spleen and skeleton. There is no consensus over ideal time for obstetric intervention. Ideal time for pregnancy termination is of major concern when assessing fetal vitality since methods used today have high false positives rate, leading to unnecessary prematurity. In extreme prematurity the decision to terminate pregnancy can lead to irreversible consequences. In an attempt to minimize damage, it was decided to carry out a review, based on the best evidence regarding conduct in fetal brain sparing effect.
Subject(s)
Humans , Female , Pregnancy , Cerebrovascular Circulation , Fetal Viability , Fetus/blood supply , Fetal Hypoxia/physiopathology , Fetal Hypoxia/blood , Placental Circulation , Ultrasonography, Doppler , Middle Cerebral Artery , Uterine Artery , Umbilical Arteries , Prognosis , Ultrasonography, PrenatalABSTRACT
El trabajo de parto es un evento de riesgo para hipoxia fetal aguda, lo que puede detectarse en alteraciones del Monitoreo Electrónico Fetal Intraparto (MEFI). Frente a un MEFI sugerente de hipoxemia fetal, existen maniobras estándar de resucitación intrauterina como lateralización de la paciente, aporte de volumen intravenoso y suspensión de la infusión oxitócica. Se debate la utilidad de la hiperoxigenación materna y la tocolisis aguda. Revisamos la evidencia científica relevante sobre la utilidad y seguridad de estas dos maniobras. Encontramos sólo limitada evidencia respecto del efecto benéfico de la hiperoxigenación materna frente a alteraciones del MEFI, existiendo dudas de su inocuidad. La tocolisis aguda ha demostrado ser eficaz en lograr la normalización del MEFI, independiente de la presencia de hiperactividad uterina, con una efectividad cercana al 80 por ciento. La evidencia apoya el uso de B-miméticos y Nitroglicerina. Recomendamos incluir en la practica clínica habitual la tocolisis aguda y la hiperoxigenación materna sólo por lapsos breves, junto a las maniobras habituales de resucitación intrauterina frente a un MEFI alterado. (
Labor is a risk condition for acute fetal hypoxia, this hypoxia can be detected by using cardiotocography (CTG). When CTG suggest hypoxia, intrauterine resuscitation techniques must be implemented, such as lateral positioning of the mother, intravenous fluid administration and suspension of oxytocin administration. Among intrauterine resuscitation techniques it is discussed the use of maternal hyperoxygenation and acute tocolysis. Here we review the evidence supporting utility and safety of these two techniques. We found only limited evidence supporting the beneficial role of maternal hyperoxygenation after nonreassuring CTG, plus concerns about its safety. Acute tocolysis has proven to be efficient in normalizing CTG, independent of the presence of uterine hyperactivity, with an overall benefit of 80 percent. Evidence supports the use of B-mimetics and nitroglycerin. We recommend to include acute tocolysis and maternal hyperoxygenation (just for limited time), among intrauterine resuscitation techniques for abnormal CTG.