Published online before print July 8, 2002, doi: 10.1161/01.RES.0000028150.51130.36
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© 2002 American Heart Association, Inc.
Cellular Biology |
Comparison of Sphingosine 1-Phosphate–Induced Intracellular Signaling Pathways in Vascular Smooth Muscles
Differential Role in Vasoconstriction
From the Department of Biomedical Sciences (F.C., R.H.S., G.F.N.), Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK; and 7TMR Systems Research Europe (A.W.), GlaxoSmithKline R&D, Stevenage, UK.
Correspondence to Graeme F. Nixon, Dept of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. E-mail g.f.nixon{at}abdn.ac.uk
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 p160ROCK (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 [Ca2+]i, initially generated via Ca2+ release from the sarcoplasmic reticulum by an inositol 1,4,5-trisphosphate–dependent pathway. In aorta VSM, a small increase in [Ca2+]i was observed after stimulation at higher concentrations of S1P. S1P induced activation of p42/p44mapk in aorta and cerebral artery VSM. Subtype-specific S1P receptor antibodies revealed that the expression of S1P3/EDG-3 and S1P2/EDG-5 receptors is 4-fold higher in cerebral artery compared with aorta. S1P1/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 • sphingosine 1-phosphate • cerebral artery • vasoconstriction
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