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1 Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston 02115; 2 Veterans Affairs Boston Healthcare System, West Roxbury, Massachusetts 02132; and 3 Second Department of Physiology, Kagawa Medical School, Kagawa, 761-0793 Japan
Sphingosine-1-phosphate (S1P)
is a platelet-derived lipid mediator that activates the
endothelial isoform of nitric oxide synthase (eNOS) in endothelial
cells. However, the role of S1P in endothelium-dependent vasodilation
and the signaling pathways elicited by S1P in intact vessels are
largely unknown. We found that S1P induces dose-dependent transient
relaxation of isolated pressurized mesenteric arterioles
(EC50 10 ± 3 nM); maximal vasodilation (55 ± 8%) is seen ~2 min after S1P addition and returns to baseline by 5 min. S1P promotes comparable responses in arterioles from wild-type but
not eNOSnull mice. S1P-induced vasodilation is abrogated by
removal of endothelium or by the addition of the NOS inhibitor
N
-monomethyl-L-arginine but is
not affected by the cyclooxygenase inhibitor indomethacin, nor by the
blockade of K+ channels by using 4-aminopyridine.
S1P-induced vasodilation is attenuated by pertussis toxin, by the
phosphoinositide 3-kinase (PI3-kinase) inhibitor wortmannin, and by the
calcium chelator BAPTA. With the use of high-sensitivity protein
immunoblots in extracts from single pressurized vessels, we found that
S1P, but not bradykinin, promotes the phosphorylation of eNOS at
Ser1179. Maximum S1P-induced eNOS Ser1179
phosphorylation was reached at the time of maximum vasorelaxation, but
enzyme phosphorylation persisted for several minutes after vasodilation
had resolved. Thus regulatory pathways distinct from eNOS
Ser1179 dephosphorylation serve to terminate
agonist-promoted vasorelaxation. Taken together, our findings
demonstrate that S1P, an important intercellular mediator of
platelet-vessel wall interactions, is a effective arteriolar
vasodilator that acts via G protein-dependent, calcium-sensitive, and
PI3-kinase-modulated signaling pathways.
sphingolipids; endothelium-dependent relaxation; nitric oxide; endothelial nitric oxide synthase phosphorylation.
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