title: Role of dual-specificity protein phosphatase-5 in modulating the myogenic response in rat cerebral arteries.
abstract: The present study examined the role of the dual-specificity protein phosphatase-5 (DUSP-5) in the pressure-induced myogenic responses of organ-cultured cerebral arterial segments. In these studies, we initially compared freshly isolated and organ-cultured cerebral arterial segments with respect to responses to step increases in intravascular pressure, vasodilator and vasoconstrictor stimuli, activities of the large-conductance arterial Ca(2+)-activated K(+) (K(Ca)) single-channel current, and stable protein expression of DUSP-5 enzyme. The results demonstrate maintained pressure-dependent myogenic vasoconstriction, DUSP-5 protein expression, endothelium-dependent and -independent dilations, agonist-induced constriction, and unitary K(Ca) channel conductance in organ-cultured cerebral arterial segments similar to that in freshly isolated cerebral arteries. Furthermore, using a permeabilization transfection technique in organ-cultured cerebral arterial segments, gene-specific small interfering RNA (siRNA) induced knockdown of DUSP-5 mRNA and protein, which were associated with enhanced pressure-dependent cerebral arterial myogenic constriction and increased phosphorylation of PKC-βII. In addition, siRNA knockdown of DUSP-5 reduced levels of phosphorylated ROCK and ERK1 with no change in the level of phosphorylated ERK2. Pharmacological inhibition of ERK1/2 phosphorylation significantly attenuated pressure-induced myogenic constriction in cerebral arteries. The findings within the present studies illustrate that DUSP-5, native in cerebral arterial muscle cells, appears to regulate signaling of pressure-dependent myogenic cerebral arterial constriction, which is crucial for the maintenance of constant cerebral blood flow to the brain.
authors.affiliation: Department of Physiology and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Nadi T
authors.initials: NT
authors.lastname: Wickramasekera
authors.forename: Debebe
authors.initials: D
authors.lastname: Gebremedhin
authors.forename: Koryn A
authors.initials: KA
authors.lastname: Carver
authors.forename: Padmanabhan
authors.initials: P
authors.lastname: Vakeel
authors.forename: Ramani
authors.initials: R
authors.lastname: Ramchandran
authors.forename: Aaron
authors.initials: A
authors.lastname: Schuett
authors.forename: David R
authors.initials: DR
authors.lastname: Harder
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000166:cytology / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D054637:Dual-Specificity Phosphatases / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D024510:Muscle Development / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054637:Dual-Specificity Phosphatases; C514214:Dusp5 protein, rat