Hypoxic Pulmonary Hypertension of the Newborn

Gao, Yuansheng; Raj, J. Usha

doi:10.1002/cphy.c090015

Cited by 16 publications

(31 citation statements)

References 297 publications

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“…It is widely recognized that regulation of P PA is influenced by postnatal age and it is unclear which mechanisms identified in the adult translate to the neonate. A recent review provided an in depth dissection of the role of hypoxia in PPHN, and the mediators and cellular mechanisms involved (203).…”

Section: Pediatric Pulmonary Hypertensionmentioning

confidence: 99%

Lung Circulation

Suresh

Shimoda

2016

Comprehensive Physiology

104

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The circulation of the lung is unique both in volume and function. For example, it is the only organ with two circulations: the pulmonary circulation, the main function of which is gas exchange, and the bronchial circulation, a systemic vascular supply that provides oxygenated blood to the walls of the conducting airways, pulmonary arteries and veins. The pulmonary circulation accommodates the entire cardiac output, maintaining high blood flow at low intravascular arterial pressure. As compared with the systemic circulation, pulmonary arteries have thinner walls with much less vascular smooth muscle and a relative lack of basal tone. Factors controlling pulmonary blood flow include vascular structure, gravity, mechanical effects of breathing, and the influence of neural and humoral factors. Pulmonary vascular tone is also altered by hypoxia, which causes pulmonary vasoconstriction. If the hypoxic stimulus persists for a prolonged period, contraction is accompanied by remodeling of the vasculature, resulting in pulmonary hypertension. In addition, genetic and environmental factors can also confer susceptibility to development of pulmonary hypertension. Under normal conditions, the endothelium forms a tight barrier, actively regulating interstitial fluid homeostasis. Infection and inflammation compromise normal barrier homeostasis, resulting in increased permeability and edema formation. This article focuses on reviewing the basics of the lung circulation (pulmonary and bronchial), normal development and transition at birth and vasoregulation. Mechanisms contributing to pathological conditions in the pulmonary circulation, in particular when barrier function is disrupted and during development of pulmonary hypertension, will also be discussed.

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Section: Pediatric Pulmonary Hypertensionmentioning

confidence: 99%

Lung Circulation

Suresh

Shimoda

2016

Comprehensive Physiology

104

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“…Both, vascular vasoconstriction and vascular remodeling end up in a significant reduction of the lumen of the intrapulmonary arteries increasing the PVR [65,67,71]. Chronic pulmonary arterial hypertension often mistaken for right ventricle hypertrophy and associates with marked endothelial dysfunction [67,72,73].…”

Section: Perinatal Cardiovascular Responses and Treatmentmentioning

confidence: 99%

Pharmacological approaches in either intermittent or permanent hypoxia: A tale of two exposures

Herrera

Farías

Ebensperger

et al. 2015

Pharmacological Research

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“…In utero, pulmonary arterial smooth muscle cells (PASMCs) are rounded and densely packed, resulting in a thick arterial wall and narrow lumen (15). The myocyte actin cytoskeleton undergoes remodeling during circulatory adaptation after birth (21), as exposure to normoxic conditions promotes actin filament disassembly to permit myocyte elongation.…”

mentioning

confidence: 99%

Thromboxane-induced actin polymerization in hypoxic neonatal pulmonary arterial myocytes involves Cdc42 signaling

Fediuk

Sikarwar

Nolette

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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In hypoxic pulmonary arterial (PA) myocytes, challenge with thromboxane mimetic U46619 induces marked actin polymerization and contraction, phenotypic features of persistent pulmonary hypertension of the newborn (PPHN). Rho GTPases regulate the actin cytoskeleton. We previously reported that U46619-induced actin polymerization in hypoxic PA myocytes occurs independently of the RhoA pathway and hypothesized involvement of the Cdc42 pathway. PA myocytes grown in normoxia or hypoxia for 72 h were stimulated with U46619, then analyzed for Rac/Cdc42 activation by affinity precipitation, phosphatidylinositide-3-kinase (PI3K) activity by phospho-Akt, phospho-p21-activated kinase (PAK) by immunoblot, and association of Cdc42 with neuronal Wiskott Aldrich Syndrome protein (N-WASp) by immunoprecipitation. The effect of Rac or PAK inhibition on filamentous actin was quantified by laser-scanning cytometry and by cytoskeletal fractionation; effects of actin-modifying agents were measured by isometric myography. Basal Cdc42 activity increased in hypoxia, whereas Rac activity decreased. U46619 challenge increased Cdc42 and Rac activity in hypoxic cells, independently of PI3K. Hypoxia increased phospho-PAK, unaltered by U46619. Association of Cdc42 with N-WASp decreased in hypoxia but increased after U46619 exposure. Hypoxia doubled filamentous-to-globular ratios of α- and γ-actin isoforms. Jasplakinolide stabilized γ-filaments, increasing force; cytochalasin D depolymerized all actin isoforms, decreasing force. Rac and PAK inhibition decreased filamentous actin in tissues although without decrease in force. Rho inhibition decreased myosin phosphorylation and force. Hypoxia induces actin polymerization in PA myocytes, particularly increasing filamentous α- and γ-actin, contributing to U46619-induced contraction. Hypoxic PA myocytes challenged with a thromboxane mimetic polymerize actin via the Cdc42 pathway, reflecting increased Cdc42 association with N-WASp. Mechanisms regulating thromboxane-mediated actin polymerization are potential targets for future PPHN pharmacotherapy.

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Hypoxic Pulmonary Hypertension of the Newborn

Cited by 16 publications

References 297 publications

Lung Circulation

Lung Circulation

Pharmacological approaches in either intermittent or permanent hypoxia: A tale of two exposures

Thromboxane-induced actin polymerization in hypoxic neonatal pulmonary arterial myocytes involves Cdc42 signaling

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