Reactive oxygen species attenuate vasoconstrictor responses in mice overexpressing p22 phox

The role of H2O2 in modulating arterial tone is complex and somewhat ambiguous, as previous studies report roles for H2O2 in both vasoconstriction and relaxation. In this study, isometric tension recording was utilized to measure force generation in response to cumulative concentrations of prostaglandin F2α and phenylephrine in denuded aortic rings obtained from male Tgp22smc mice (bred to overexpress the p22phox subunit of the NAD(P)H oxidase selectively in VSMC) and negative controls (WT). We tested the hypothesis that overexpression of p22phox, which increases VSMC H2O2 production, would lead to altered vasoconstrictor responses. In the absence of any change in vascular sensitivity, overexpression of p22phox resulted in decreased contractile force generation in response to both agonists. Pretreatment with PEG-catalase normalized contractile responses in rings from Tgp22smc mice implicating ROS as a mediator of the attenuated vasoconstrictor responses. Ca2+-sensitization via Rho-kinase activity, K+ and Ca2+ channel function in rings from Tgp22smc mice were unaffected by the increased ROS. Conversely, PKC inhibition attenuated constrictor responses significantly more in rings from WT than Tgp22smc mice, suggesting that chronically elevated vascular H2O2 may reduce PKC activity that results in decreased agonist-mediated force generation in the vasculature of Tgp22smc mice. (AHA-SDG 03300119N)