RESUMO
Decreased angiogenesis contributes to persistent pulmonary hypertension of the newborn (PPHN); mechanisms remain unclear. AMPK (5'AMP activated protein kinase) is a key regulator of cell metabolism. We investigated the hypothesis that a decrease in AMPK function leads to mitochondrial dysfunction and altered balance of notch ligands delta-like 4 (DLL4) and Jagged 1 (Jag1) to impair angiogenesis in PPHN. Studies were done in fetal lambs with PPHN induced by prenatal ductus arteriosus constriction and gestation-matched control lambs. PPHN lambs were treated with saline or AMPK agonist metformin. Angiogenesis was assessed in lungs with micro-computed tomography angiography and histology. AMPK function; expression of mitochondrial electron transport chain (ETC) complex proteins I-V, Dll4, and Jag1; mitochondrial number; and in vitro angiogenesis function were assessed in pulmonary artery endothelial cells (PAEC) from control and PPHN lambs. AMPK function was decreased in PPHN PAEC and lung sections. Expression of mitochondrial transcription factor, PGC-1α, ETC complex proteins I-V, and mitochondrial number were decreased in PPHN. In vitro angiogenesis of PAEC and capillary number and vessel volume fraction in the lung were decreased in PPHN. Expression of DLL4 was increased and Jag1 was decreased in PAEC from PPHN lambs. AMPK agonists A769662 and metformin increased the mitochondrial complex proteins and number, in vitro angiogenesis, and Jag1 levels and decreased DLL4 levels in PPHN PAEC. Infusion of metformin in vivo increased the vessel density in PPHN lungs. Decreased AMPK function contributes to impaired angiogenesis in PPHN by altered balance of notch ligands in PPHN.
Assuntos
Células Endoteliais/enzimologia , Hipertensão Pulmonar/enzimologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Jagged-1/metabolismo , Proteínas de Membrana/metabolismo , Neovascularização Patológica/enzimologia , Síndrome da Persistência do Padrão de Circulação Fetal/enzimologia , Proteínas Quinases/metabolismo , Receptores Notch/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Animais , Animais Recém-Nascidos , Compostos de Bifenilo , Canal Arterial/embriologia , Canal Arterial/cirurgia , Transporte de Elétrons , Ativação Enzimática , Feminino , Hipertensão Pulmonar/fisiopatologia , Ligantes , Pulmão/patologia , Metformina/farmacologia , Metformina/uso terapêutico , Mitocôndrias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Síndrome da Persistência do Padrão de Circulação Fetal/tratamento farmacológico , Síndrome da Persistência do Padrão de Circulação Fetal/patologia , Síndrome da Persistência do Padrão de Circulação Fetal/fisiopatologia , Fosforilação , Gravidez , Proteínas Quinases/fisiologia , Pironas/farmacologia , Ovinos , Tiofenos/farmacologia , Treonina/metabolismo , TransfecçãoRESUMO
Inhaled nitric oxide (iNO) therapy had a transformational impact on the management of infants with persistent pulmonary hypertension of the newborn (PPHN). iNO remains the only approved pulmonary vasodilator for PPHN; yet 30% to 40% of patients do not respond or have incomplete response to iNO. Lung recruitment strategies with early surfactant administration and high-frequency ventilation can optimize the response to iNO in the presence of parenchymal lung diseases. Alternate pulmonary vasodilators are used commonly as rescue, life-saving measures, though there is a lack of high-quality evidence supporting their efficacy and safety. This article reviews the available evidence and future directions for research in PPHN.