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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2043.)
© 2006 American Heart Association, Inc.

Vascular Biology

Sphingosine Kinase–Dependent Activation of Endothelial Nitric Oxide Synthase by Angiotensin II

Arthur C.M. Mulders; Mariëlle C. Hendriks-Balk; Marie-Jeanne Mathy; Martin C. Michel; Astrid E. Alewijnse; Stephan L.M. Peters

From the Department of Pharmacology and Pharmacotherapy, University of Amsterdam, Academic Medical Center, Amsterdam, Netherlands.

Correspondence to Stephan L.M. Peters, PhD, Department of Pharmacology and Pharmacotherapy, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, Netherlands. E-mail S.L.Peters{at}amc.uva.nl

Objective— In addition to their role in programmed cell death, cell survival, and cell growth, sphingolipid metabolites such as ceramide, sphingosine, and sphingosine-1-phosphate have vasoactive properties. Besides their occurrence in blood, they can also be formed locally in the vascular wall itself in response to external stimuli. This study was performed to investigate whether vasoactive compounds modulate sphingolipid metabolism in the vascular wall and how this might contribute to the vascular responses.

Methods and Results— In isolated rat carotid arteries, the contractile responses to angiotensin II are enhanced by the sphingosine kinase inhibitor dimethylsphingosine. Endothelium removal or NO synthase inhibition by N-nitro-L-arginine results in a similar enhancement. Angiotensin II concentration-dependently induces NO production in an endothelial cell line, which can be diminished by dimethylsphingosine. Using immunoblotting and intracellular calcium measurements, we demonstrate that this sphingosine kinase–dependent endothelial NO synthase activation is mediated via both phosphatidylinositol 3-kinase/Akt and calcium-dependent pathways.

Conclusions— Angiotensin II induces a sphingosine kinase–dependent activation of endothelial NO synthase, which partially counteracts the contractile responses in isolated artery preparations. This pathway may be of importance under pathological circumstances with reduced NO bioavailability. Moreover, a disturbed sphingolipid metabolism in the vascular wall may lead to reduced NO bioavailability and endothelial dysfunction.

Sphingolipid metabolites can be formed locally in the vascular wall. AT₁ receptor stimulation by angiotensin II induces a sphingosine kinase–dependent endothelial NO synthase activation via phosphatidylinositol 3-kinase/Akt and calcium-dependent pathways. This may be of importance during, or alternatively under pathological circumstances leading to, reduced NO bioavailability and endothelial dysfunction.

Key Words: sphingosine kinase • sphingosine-1–phosphate • angiotensins • nitric oxide synthase • vasoconstriction

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