title: Redox signaling via oxidative inactivation of PTEN modulates pressure-dependent myogenic tone in rat middle cerebral arteries.
abstract: The present study examined the level of generation of reactive oxygen species (ROS) and roles of inactivation of the phosphatase PTEN and the PI3K/Akt signaling pathway in response to an increase in intramural pressure-induced myogenic cerebral arterial constriction. Step increases in intraluminal pressure of cannulated cerebral arteries induced myogenic constriction and concomitant formation of superoxide (O2 (.-)) and its dismutation product hydrogen peroxide (H2O2) as determined by fluorescent HPLC analysis, microscopic analysis of intensity of dihydroethidium fluorescence and attenuation of pressure-induced myogenic constriction by pretreatment with the ROS scavenger 4,hydroxyl-2,2,6,6-tetramethylpiperidine1-oxyl (tempol) or Mito-tempol or MitoQ in the presence or absence of PEG-catalase. An increase in intraluminal pressure induced oxidation of 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 [Ca(2+)]i level in freshly isolated cerebral arterial muscle cells (CAMCs), responses that were attenuated by Inhibition of the PI3K/Akt pathway. These findings demonstrate an increase in intraluminal pressure induced increase in ROS production triggered redox-sensitive signaling mechanism emanating from the cross-talk between oxidative inactivation of PTEN and activation of the PI3K/Akt signaling pathway that involves in the regulation of pressure-dependent myogenic cerebral arterial constriction.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. mariyei@mcw.edu
authors.forename: Debebe
authors.initials: D
authors.lastname: Gebremedhin
authors.forename: Maia
authors.initials: M
authors.lastname: Terashvili
authors.forename: Nadi
authors.initials: N
authors.lastname: Wickramasekera
authors.forename: David X
authors.initials: DX
authors.lastname: Zhang
authors.forename: Nicole
authors.initials: N
authors.lastname: Rau
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miura
authors.forename: David R
authors.initials: DR
authors.lastname: Harder
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D011312:Pressure; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
chemical_list: D024681:Potassium Channels, Calcium-Activated; D017382:Reactive Oxygen Species; C070295:catalase-polyethylene glycol; D013481:Superoxides; D011092:Polyethylene Glycols; D006861:Hydrogen Peroxide; D002374:Catalase; D051059:PTEN Phosphohydrolase; D002118:Calcium