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Augmented pulmonary vasoconstrictor reactivity following chronic hypoxia requires Src kinase and EGFR signaling.

RATIONALE
Chronic hypoxia augments pressure- and agonist-induced pulmonary vasoconstriction through myofilament calcium sensitization. NADPH oxidases contribute to the development of pulmonary hypertension, and both epidermal growth factor receptor and Src kinases can regulate NADPH oxidase.


OBJECTIVES
We tested the hypothesis that Src/epidermal growth factor receptor signaling mediates enhanced vasoconstrictor sensitivity following chronic hypoxia through NADPH oxidase-derived superoxide generation.


METHODS
Protocols employed pharmacological inhibitors in isolated, pressurized rat pulmonary arteries to examine the contribution of a variety of signaling moieties to enhanced vascular tone following chronic hypoxia. Superoxide generation in pulmonary arterial smooth muscle cells was assessed using the fluorescent indicator dihydroethidium. Indices of pulmonary hypertension were measured in rats treated with the epidermal growth factor receptor inhibitor gefitinib.


MEASUREMENTS AND RESULTS
Inhibition of NADPH oxidase, Rac1, and epidermal growth factor receptor abolished pressure-induced pulmonary arterial tone and endothelin-1-dependent calcium sensitization and vasoconstriction following chronic hypoxia. Consistently, chronic hypoxia augmented endothelin-1-induced superoxide production through epidermal growth factor receptor signaling, and rats treated chronically with gefitinib displayed reduced right ventricular pressure and diminished arterial remodeling. Src kinases were additionally activated by ET-1 following chronic hypoxia and contributed to enhanced basal arterial tone and vasoconstriction to ET-1. A role for matrix metalloproteinase 2 to mediate Src dependent-epidermal growth factor receptor activation is further supported by our findings.


CONCLUSIONS
Our studies support a novel role for a Src kinase, epidermal growth factor receptor, NADPH oxidase signaling axis to mediate enhanced pulmonary vascular smooth muscle Ca2+ sensitization, vasoconstriction, and pulmonary hypertension following chronic hypoxia.