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|Title:||Sphingosine kinase functionally links elevated transmural pressure and increased reactive oxygen species formation in resistance arteries|
|Citation:||FASEB Journal, 2006; 20(6):1-20|
|Publisher:||Federation of American Societies for Experimental Biology|
|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|
|Appears in Collections:||Agriculture, Food and Wine publications|
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