Decreased Gene Expression of Endothelial Nitric Oxide Synthase in Newborns with Persistent Pulmonary Hypertension

Villanueva, Maria Esterlita T; Zaher, Fadi M.; Svinarich, David M.; Konduri, Girija G.

doi:10.1203/00006450-199809000-00012

Cited by 81 publications

(42 citation statements)

References 13 publications

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“…†P Ͻ 0.05 vs. stretch Veh. (30,45). Antenatal surgical closure of the ductus arteriosus in fetal lambs alters lung vascular reactivity and structure, causes failure of postnatal adaptation at delivery, and provides an important experimental model of PPHN (1,28,34).…”

Section: Discussionmentioning

confidence: 99%

Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells

Wedgwood

Lakshminrusimha

Schumacker

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Wedgwood S, Lakshminrusimha S, Schumacker PT, Steinhorn RH. Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 309: L196 -L203, 2015. First published May 29, 2015 doi:10.1152/ajplung.00097.2014.-This study was designed to determine whether cyclic stretch induces a persistent pulmonary hypertension of the newborn (PPHN) phenotype of increased NADPH oxidase (Nox) 4 signaling in control pulmonary artery smooth muscle cells (PASMC), and to identify the signal transduction molecules involved. To achieve this, PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and PASMC were isolated from control (twin) and PPHN lambs. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h. Stretch-induced Nox4 expression was attenuated by inhibition of mitochondrial complex III and NF-B, and stretch-induced protein thiol oxidation was attenuated by Nox4 small interfering RNA and complex III inhibition. NF-B activity was increased by stretch in a complex III-dependent fashion, and stretch-induced cyclin D1 expression was attenuated by complex III inhibition and Nox4 small interfering RNA. This is the first study to show that cyclic stretch increases Nox4 expression via mitochondrial complex III-induced activation of NF-B in fetal PASMC, resulting in ROS signaling and increased cyclin D1 expression. Targeting these signaling molecules may attenuate pulmonary vascular remodeling associated with PPHN. pulmonary hypertension; reactive oxygen species; NADPH oxidase AT BIRTH, PULMONARY VASCULAR resistance must rapidly decrease, to allow pulmonary blood flow to increase 10-fold and establish the lung as the organ of gas exchange. This fetal-tonewborn transition is regulated by complex physiological and biochemical processes, which are necessary to promote pulmonary artery (PA) vasodilation. Abnormalities in the transition at birth produce persistent pulmonary hypertension of the newborn (PPHN), a life-threatening clinical disorder of newborn infants (41). PPHN is characterized by elevated pulmonary vascular resistance (PVR), right-to-left extrapulmonary shunting of deoxygenated blood, and life-threatening hypoxemia. Pathological findings include pulmonary vascular remodeling and smooth muscle hyperplasia (20), and the severity of the disease correlates with the extent of vascular remodeling. However, the abnormal in utero events that trigger the development of PPHN are poorly understood.A lamb model involving antenatal ligation of the ductus arteriosus followed by delivery at near-term gestation has been used to simulate PPHN. These newborn lambs display pulmonary vascular remodeling, increased PA pressure, and other physiological changes consistent with clinical PPHN (33, 52). Ductal ligation initially induces a large increase in pulmonary blood flow followed by a return to baseline flow while PA pressure remains high (1). In vivo experiments s...

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Section: Discussionmentioning

confidence: 99%

Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells

Wedgwood

Lakshminrusimha

Schumacker

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…[10][11][12][13] These diseases contribute greatly to the morbidity and mortality observed in neonatal intensive care units. Quantification of the number of ECFCs and study of the function of these cells compared with healthy controls will likely yield new and important information regarding the role of endothelial cells in the pathogenesis of these newborn diseases and their utility as a marker of either disease progression or morbidities.…”

Section: Introductionmentioning

confidence: 99%

Endothelial colony-forming cells and mesenchymal stem cells from ECMO circuits of term infants

et al. 2010

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Objective: Endothelial progenitor cells (EPCs) have been examined in numerous adult diseases and have been suggested as a cellular-based therapy. However, there are no reports describing EPCs being isolated from newborn peripheral blood.Study Design: Endothelial colony-forming cells (ECFCs), a subtype of EPCs, were isolated from blood collected from 12 neonatal extracorporeal membrane oxygenation (ECMO) circuits.Result: ECFCs were isolated in all samples. We unexpectedly isolated a distinctly different colony of mesenchymal stem cells (MSCs) in seven samples. Both cell types expressed the expected endothelial or mesenchymal cell surface antigens. Conclusion:To our knowledge, this is the first report of ECFCs and MSCs isolated from peripheral blood of critically ill term newborns. Both cells types may be mobilized in response to critical illness or to the ECMO circuit. Further studies evaluating the role of stem cells in various newborn conditions are warranted.

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“…Decreased eNOS expression has also been reported in umbilical venous endothelial cell cultures from human infants with meconium staining who develop PPHN [31]. Meconium components incite an inflammatory response with release of cytokines and increase the production of vasoconstrictors including endothelin and thromboxane [32].…”

Section: Pathophysiology Of Pphnmentioning

confidence: 93%

Persistent Pulmonary Hypertension of the Newborn

Nair

Bataclan²

1998

Key Topics in Neonatology

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Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance resulting in right-to-left shunting of blood and hypoxemia. PPHN is often secondary to parenchymal lung disease (such as meconium aspiration syndrome, pneumonia or respiratory distress syndrome) or lung hypoplasia (with congenital diaphragmatic hernia or oligohydramnios) but can also be idiopathic. The diagnosis of PPHN is based on clinical evidence of labile hypoxemia often associated with differential cyanosis. The diagnosis is confirmed by the echocardiographic demonstration of -(a) right-to-left or bidirectional shunt at the ductus or foramen ovale and/or, (b) flattening or leftward deviation of the interventricular septum and/or, (c) tricuspid regurgitation, and finally (d) absence of structural heart disease. Management strategies include optimal oxygenation, avoiding respiratory and metabolic acidosis, blood pressure stabilization, sedation and pulmonary vasodilator therapy. Failure of these measures would lead to consideration of extracorporeal membrane oxygenation (ECMO); however decreased need for this rescue therapy has been documented with advances in medical management. While trends also note improved survival, long-term neurodevelopmental disabilities such as deafness and learning disabilities remain a concern in many infants with severe PPHN. Funded by: 1R01HD072929-0 (SL)

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Decreased Gene Expression of Endothelial Nitric Oxide Synthase in Newborns with Persistent Pulmonary Hypertension

Cited by 81 publications

References 13 publications

Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells

Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells

Endothelial colony-forming cells and mesenchymal stem cells from ECMO circuits of term infants

Persistent Pulmonary Hypertension of the Newborn

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