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https://hdl.handle.net/2440/23882
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Type: | Journal article |
Title: | Sphingosine kinase functionally links elevated transmural pressure and increased reactive oxygen species formation in resistance arteries |
Author: | Keller, M. Lidington, D. Vogel, L. Peter, B. Sohn, H. Pagano, P. Pitson, S. Spiegel, S. Pohl, U. Bolz, S. |
Citation: | The FASEB Journal, 2006; 20(6):1-20 |
Publisher: | Federation of American Societies for Experimental Biology |
Issue Date: | 2006 |
ISSN: | 0892-6638 1530-6860 |
Statement of Responsibility: | Matthias Keller, Darcy Lidington, Lukas Vogel, Bernhard Friedrich Peter, Hae-Young Sohn, Patrick J. Pagano, Stuart Pitson, Sarah Spiegel, Ulrich Pohl, and Steffen-Sebastian Bolz |
Abstract: | Myogenic 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. |
Keywords: | smooth muscle signal transduction transfection NADPH oxidase Ca²⁺ sensitization |
Description: | Published online February 13, 2006 |
Rights: | ©2006 FASEB |
DOI: | 10.1096/fj.05-4075fje |
Published version: | http://dx.doi.org/10.1096/fj.05-4075fje |
Appears in Collections: | Agriculture, Food and Wine publications Aurora harvest 2 |
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