Abstract-Sphingosine 1-phosphate (S1P), a lipid released from activated platelets, influences physiological processes in the cardiovascular system via activation of the endothelial differentiation gene (EDG/S1P) family of 7 transmembrane G protein-coupled receptors. In cultured vascular smooth muscle (VSM) cells, S1P signaling has been shown to stimulate proliferative responses; however, its role in vasoconstriction has not been examined. In the present study, the effects of S1P and EDG/S1P receptor expression were determined in rat VSM from cerebral artery and aorta. S1P induced constriction of cerebral artery, which was partly dependent on activation of p160 ROCK (Rho-kinase). S1P also induced activation of RhoA in cerebral artery with a similar time course to contraction. In aorta, S1P did not produce a constriction or RhoA activation. In VSM myocytes from cerebral arteries, stimulation with S1P gives rise to a global increase in [Ca 2ϩ ] i , initially generated via Ca 2ϩ release from the sarcoplasmic reticulum by an inositol 1,4,5-trisphosphate-dependent pathway. In aorta VSM, a small increase in [Ca 2ϩ ] i was observed after stimulation at higher concentrations of S1P. S1P induced activation of p42/p44 mapk in aorta and cerebral artery VSM. Subtype-specific S1P receptor antibodies revealed that the expression of S1P 3 /EDG-3 and S1P 2 /EDG-5 receptors is 4-fold higher in cerebral artery compared with aorta. S1P 1 /EDG-1 receptor expression was similar in both types of VSM. Therefore, the ability of S1P to act as a vasoactive mediator is dependent on the activation of associated signaling pathways and may vary in different VSM. This differential signaling may be related to the expression of S1P receptor subtypes. Key Words: vascular smooth muscle Ⅲ sphingosine 1-phosphate Ⅲ cerebral artery Ⅲ vasoconstriction S everal studies have now shown that the bioactive sphingolipid, sphingosine 1-phosphate (S1P), is likely to play an important role in regulating cellular processes via activation of specific signal transduction pathways. [1][2][3] In the shortterm, S1P-induced activation of several intracellular signaling pathways occurs, such as an increase in the intracellular calcium concentration ([Ca 2ϩ ] i ), 4 activation of the monomeric GTP-binding protein, p21RhoA (RhoA), 5 and activation of p42/p44 mitogen-activated protein kinase (p42/p44 mapk ). 6,7 Through activation of these signaling pathways, S1P can induce longer term effects, such as proliferation, differentiation, and cell migration. 1 It is now clear that S1P-induced intracellular effects occur predominantly through activation of selective S1P receptors on the plasma membrane. 2 These receptors, belonging to the G protein-coupled receptor superfamily, originally known as EDG (endothelial differentiation gene) receptors. 8 Several isoforms have now been cloned and S1P 1 /EDG-1, 5 S1P 2 / EDG-5, 9 S1P 3 /EDG-3, 10 S1P 4 /EDG-6, 11 and S1P 5 /EDG-8 12 have high affinities for S1P with EC 50 s in the nmol/L range.Recent studies have investigated th...

While the roles of subtypes 1 and 2 of the ryanodine receptors (RYRs) have been studied in cellular systems expressing specifically one or the other of these subtypes (i.e. skeletal and cardiac muscle), the function of these receptors has not been evaluated in smooth muscles.

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