Chronic hypoxia augments depolarization-induced Ca2+ sensitization in pulmonary vascular smooth muscle through superoxide-dependent stimulation of RhoA

Bradley Randal Scott Broughton, Nikki L Jernigan, Charles E Norton, Benjimen R Walker, Thomas C Resta

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Abstract

Chronic hypoxia augments depolarization-induced Ca2+ sensitization in pulmonary vascular smooth muscle through superoxide-dependent stimulation of RhoA. Rho kinase (ROCK)-dependent vasoconstriction has been implicated as a major factor in chronic hypoxia (CH)-induced pulmonary hypertension. This component of pulmonary hypertension is associated with arterial myogenicity and increased vasoreactivity to receptor-mediated agonists and depolarizing stimuli resulting from ROCK-dependent myofilament Ca2+ sensitization. On the basis of separate lines of evidence that CH increases pulmonary arterial superoxide (O-2) generation and that O2+ stimulates RhoA/ROCK signaling in vascular smooth muscle (VSM), we hypothesized that depolarization-induced O2- generation mediates enhanced RhoA-dependent Ca2 sensitization in pulmonary VSM following CH. To test this hypothesis, we determined effects of the ROCK inhibitor HA-1077 and the O2- -specific spin trap tiron on vasoconstrictor reactivity to depolarizing concentrations of KCl in isolated lungs and Ca2- -permeabilized, pressurized small pulmonary arteries from control and CH (4 wk at 0.5 atm) rats. Using the same vessel preparation, we....
Original languageEnglish
Pages (from-to)232 - 242
Number of pages11
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume298
Issue number2
DOIs
Publication statusPublished - 2010

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