Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/23882
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dc.contributor.authorKeller, M.-
dc.contributor.authorLidington, D.-
dc.contributor.authorVogel, L.-
dc.contributor.authorPeter, B.-
dc.contributor.authorSohn, H.-
dc.contributor.authorPagano, P.-
dc.contributor.authorPitson, S.-
dc.contributor.authorSpiegel, S.-
dc.contributor.authorPohl, U.-
dc.contributor.authorBolz, S.-
dc.date.issued2006-
dc.identifier.citationThe FASEB Journal, 2006; 20(6):1-20-
dc.identifier.issn0892-6638-
dc.identifier.issn1530-6860-
dc.identifier.urihttp://hdl.handle.net/2440/23882-
dc.descriptionPublished online February 13, 2006-
dc.description.abstractMyogenic vasoconstriction, an intrinsic response to elevated transmural pressure (TMP), requires the activation of sphingosine kinase (Sk1) and the generation of reactive oxygen species (ROS). We hypothesized that pressure-induced Sk1 signaling and ROS generation are functionally linked. Using a model of cannulated resistance arteries isolated from the hamster gracilis muscle, we monitored vessel diameter and smooth muscle cell (SMC) Ca²⁺ i (Fura-2) or ROS production (dichlorodihydrofluorescein). Elevation of TMP stimulated the translocation of a GFP-tagged Sk1 fusion protein from the cytosol to the plasma membrane, indicative of enzymatic activation. Concurrently, elevation of TMP initiated a rapid and transient production of ROS, which was enhanced by expression of wild-type Sk1 (hSkwt) and inhibited by its dominant-negative mutant (hSkG82D). Exogenous sphingosine-1-phosphate (S1P) also stimulated ROS generation is isolated vessels. Chemical (1μmol/L DPI), peptide (gp91ds-tat/gp91ds), and genetic (N17Rac) inhibition strategies indicated that NADPH oxidase was the source of the pressure-induced ROS. NADPH oxidase inhibition attenuated myogenic vasoconstriction and reduced the apparent Ca²⁺ sensitivity of the SMC contractile apparatus, without affecting Ca²⁺-independent, RhoAmediated vasoconstriction in response to exogenous S1P. Our results indicate a mandatory role for Sk1/S1P in mediating pressure-induced, NADPH oxidase-derived ROS formation. In turn, ROS generation appears to increase Ca²⁺ sensitivity, necessary for full myogenic vasoconstriction.-
dc.description.statementofresponsibilityMatthias Keller, Darcy Lidington, Lukas Vogel, Bernhard Friedrich Peter, Hae-Young Sohn, Patrick J. Pagano, Stuart Pitson, Sarah Spiegel, Ulrich Pohl, and Steffen-Sebastian Bolz-
dc.language.isoen-
dc.publisherFederation of American Societies for Experimental Biology-
dc.rights©2006 FASEB-
dc.source.urihttp://dx.doi.org/10.1096/fj.05-4075fje-
dc.subjectsmooth muscle-
dc.subjectsignal transduction-
dc.subjecttransfection-
dc.subjectNADPH oxidase-
dc.subjectCa²⁺ sensitization-
dc.titleSphingosine kinase functionally links elevated transmural pressure and increased reactive oxygen species formation in resistance arteries-
dc.typeJournal article-
dc.identifier.doi10.1096/fj.05-4075fje-
pubs.publication-statusPublished-
dc.identifier.orcidPitson, S. [0000-0002-9527-2740]-
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