Biomedical Sciences ETDs

Publication Date

5-1-2015

Abstract

CH results in pressure dependent basal tone and enhanced depolarization- and endothelin-1 (ET-1)-induced vasoconstriction in the pulmonary circulation through Rho kinase (ROK)-dependent Ca2+ sensitization, responses that may contribute to the development of pulmonary hypertension (PH) in this setting. The free radical superoxide (O2-) has been implicated in these responses. Because NADPH oxidases (NOX) play a role in the development of PH, we hypothesized that membrane depolarization, increases in intraluminal pressure, and ET-1 signaling lead to pulmonary vascular smooth muscle (VSM) myofilament Ca2+ sensitization and augmented vasoconstrictor reactivity following CH through NOX-derived O2- production. As epidermal growth factor receptor (EGFR) and Src kinases can mediate NOX activation, we further hypothesized that Src-induced EGFR activation mediates this response. Vasoconstrictor responses to ET-1 and KCl were greater in Ca2+ permeabilized, endothelium-disrupted, pressurized, pulmonary arteries from CH (4 wk at 0.5 atm) rats compared to controls, and this effect of CH was abolished by NOX inhibition. NOX inhibition additionally prevented KCl-dependent O2- production in CH arteries. Furthermore, inhibition of EGFR and Src kinases also prevented augmented ET-1- and KCl-induced vasoconstriction and the development of basal tone. Rats treated chronically with an EGFR inhibitor (gefitinib) displayed reduced right ventricular pressure and diminished arterial remodeling associated with CH-dependent PH. We additionally determined that vascular smooth muscle membrane depolarization contributes to basal tone but not vasoconstriction to ET-1 in CH arteries by clamping membrane potential with valinomycin. Our studies support a novel role for a Src kinase/EGFR/NOX 2 signaling axis in the enhanced pulmonary vascular smooth muscle VSM Ca2+ sensitization, vasoconstriction and PH following CH.

Keywords

chronic hypoxia, pulmonary vasoconstriction, reactive oxygen species, epidermal growth factor receptor

Sponsors

American Heart Association, National Institutes of Health

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Jernigan, Nikki

Second Committee Member

Walker, Benjimen

Third Committee Member

Shuttleworth, Willaim

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