RGD Reference Report - Enhanced Depolarization-Induced Pulmonary Vasoconstriction Following Chronic Hypoxia Requires EGFR-Dependent Activation of NAD(P)H Oxidase 2. - Rat Genome Database

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Enhanced Depolarization-Induced Pulmonary Vasoconstriction Following Chronic Hypoxia Requires EGFR-Dependent Activation of NAD(P)H Oxidase 2.

Authors: Norton, CE  Broughton, BR  Jernigan, NL  Walker, BR  Resta, TC 
Citation: Norton CE, etal., Antioxid Redox Signal. 2012 Oct 18.
RGD ID: 7204494
Pubmed: PMID:22966991   (View Abstract at PubMed)
PMCID: PMC3619151   (View Article at PubMed Central)
DOI: DOI:10.1089/ars.2012.4836   (Journal Full-text)

Abstract Aims: Chronic hypoxia (CH) enhances depolarization-induced myofilament Ca(2+) sensitization and resultant pulmonary arterial constriction through superoxide (O(2)(-))-dependent stimulation of RhoA. Because NAD(P)H oxidase (NOX) has been implicated in the development of pulmonary hypertension, we hypothesized that vascular smooth muscle (VSM) depolarization increases NOX-derived O(2)(-) production leading to myofilament Ca(2+) sensitization and augmented vasoconstrictor reactivity following CH. As epidermal growth factor receptor (EGFR) mediates Rac1-dependent NOX activation in renal mesangial cells, we further sought to examine the role EGFR plays in this response. Results: Vasoconstrictor responses to depolarizing concentrations of KCl were greater in lungs isolated from CH (4 wk, 0.5 atm) rats compared to normoxic controls, and this effect of CH was abolished by the general NOX inhibitor, apocynin. CH similarly augmented KCl-induced vasoconstriction and O(2)(-) generation (assessed using the fluorescent indicator, dihydroethidium) in Ca(2+)-permeabilized, pressurized small pulmonary arteries. These latter responses to CH were prevented by general inhibition of NOX isoforms (apocynin, diphenylene iodonium), and by selective inhibition of NOX 2 (gp91ds-tat), Rac1 (NSC 23766), and EGFR (AG 1478). Consistent with these observations, CH increased KCl-induced EGFR phosphorylation, and augmented depolarization-induced Rac1 activation in an EGFR-dependent manner. Innovation: This study establishes a novel signaling axis in VSM linking membrane depolarization to contraction that is independent of Ca(2+) influx, and which mediates myofilament Ca(2+) sensitization in the hypertensive pulmonary circulation. Conclusion: CH augments membrane depolarization-induced pulmonary VSM Ca(2+) sensitization and vasoconstriction through EGFR-dependent stimulation of Rac1 and NOX 2. Antioxid. Redox Signal. 00, 000-000.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of superoxide anion generation  IMP 7204494 RGD 
positive regulation of vasoconstriction  IMP 7204494 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Egfr  (epidermal growth factor receptor)


Additional Information