S1P3 receptors mediate the potent constriction of cerebral arteries by sphingosine-1-phosphate

We characterized the effect of Sphingosine-1-phosphate (SIP) on vascular tone. SIP selectively constricted isolated cerebral, but not peripheral arteries, despite ubiquitous expression of S1P(1), S1P(2), S1P(3) and S1P(5) receptor mRNA. Clostridium B and C3 toxins and the rhokinase inhibitor Y27632 (trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexane carboxamide) reduced this vasoconstriction to S1P, indicating that the response was mediated through Rho. Pertussis toxin displayed only weak inhibition, suggesting minor involvement of G(i/o) protein. The S1P effect was specifically reduced by adenovirus bearing a slp(3) but not slp(2), antisense construct. Furthermore, suramin, which selectively blocks S1P(3) receptors, inhibited the vasoconstrictor effect of S1P, indicating that S1P(3) receptors account for at least part of S1P-mediated vasoconstriction in cerebral arteries. In vivo, intracarotid injection of S1P decreased cerebral blood flow, an effect prevented by suramin treatment. Because SIP constricts cerebral blood vessels and is released from platelets during clotting, the S1P/S1P3 System constitutes a novel potential target for cerebrovascular disease therapy. (C) 2003 Elsevier Science B.V. All rights reserved.