Modulation of pressure‐dependent cerebral arterial myogenic tone by a redox‐sensitive signaling event (1079.8)

Abstract

The objective of this study is to investigate the pressure‐induced redox‐sensitive signaling pathway in the regulation of pressure‐dependent myogenic rat cerebral arterial constriction.Methods. We have investigated effects of step increases in intramural pressure on the generation of ROS and the role of inactivation of the phosphatase PTEN and subsequent activation of the PI3K/Akt signaling pathway in pressure‐induced myogenic constriction of cerebral arteries using a battery of experimental methods.Results. Step increase in intraluminal pressure induced myogenic constriction associated with increased formation of superoxide (O2.‐) and its dismutation product hydrogen peroxide (H2O2). The increase in intraluminal pressure also induced oxidative inactivation of the lipid dual‐phosphatase PTEN and activation of Akt. Pharmacological inhibition of endogenous PTEN activity potentiated pressure‐dependent myogenic constriction, and caused a reduction in NPo of a 238 pS arterial KCa channel current and an increase in [Ca2+]i level in freshly isolated cerebral arterial muscle cells (CAMCs), responses that were attenuated by Inhibition of the PI3K/Akt pathway.Conclusions. We report that an increase in intraluminal pressure‐induced elevated O2.‐production that resulted in oxidative inactivation of PTEN and activation of the PI3K/Akt signaling pathway, which involved in modulation of the development of pressure‐dependent myogenic cerebral arterial constriction.Grant Funding Source: This work is supported by grants from NIH (R01 NIH/NHLBI, HL033833, HL092105 and HL105997)