Sphingosine kinase-dependent activation of endothelial nitric oxide synthase by angiotensin II.
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.


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(omega)-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.
Mulders
Arthur C M
AC
Department of Pharmacology and Pharmacotherapy, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
Hendriks-Balk
Mariëlle C
MC
Mathy
Marie-Jeanne
MJ
Michel
Martin C
MC
Alewijnse
Astrid E
AE
Peters
Stephan L M
SL
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002339:Carotid Arteries / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009994:Osmolar Concentration; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D000099157:Sphingosine Kinase
D000804:Angiotensin II; D002118:Calcium; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D017853:Phosphotransferases (Alcohol Group Acceptor); D051057:Proto-Oncogene Proteins c-akt; D049349:Receptors, Lysosphingolipid; D014662:Vasoconstrictor Agents; D000099157:Sphingosine Kinase