Signal transduction underlying the vascular effects of sphingosine 1-phosphate and sphingosylphosphorylcholine.
Two related lysosphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) mediate diverse cellular responses through signals transduced by either activation of G-protein coupled receptors or possibly by acting intracellularly. Vascular responses to S1P and SPC measured both in vivo and in dissected vessels show predominantly vasoconstriction with some evidence for vasodilation. Although stimulation with S1P or SPC generally leads to similar vascular responses, the signalling pathways stimulated to produce these responses are often distinct. Nevertheless, mobilization of Ca2+ from intracellular stores and influx of extracellular Ca2+, which both increase [Ca2+]i, occur in response to S1P and SPC. Both mobilization of Ca2+ from intracellular stores and influx of extracellular Ca2+ occur in response to S1P and SPC. As well, both S1P and SPC induce Ca2+-sensitization in vascular smooth muscle which is mediated through Rho kinase activation. In the endothelium, S1P and SPC stimulate the production of the vasodilator, nitric oxide through activation of endothelial nitric oxide synthase. This activation occurs through phosphorylation by Akt and through binding of Ca2+-calmodulin upon increased [Ca2+]i. These lysosphingolipids also activate cyclooxygenase-2 which produces prostaglandins with both vasoconstrictor and vasodilator properties. A balance between the signals inducing vasodilation versus the signals inducing vasoconstriction will determine the vascular outcome. Thus, perturbations in S1P and SPC concentrations, relative expression of receptors or downstream signalling pathways may provide a mechanism for pathophysiological conditions such as hypertension. Given this background, recent studies examining a potential role for S1P and SPC in hypertension and vascular dysfunction in aging are discussed.
Department Obstetrics and Gynecology, Perinatal Research Centre, University of Alberta, 227 Heritage Medical Research Center, T6G 2S2, Edmonton, Alberta, Canada. denise.hemmings@ualberta.ca
Denise G
DG
Hemmings
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; C060506:sphingosine 1-phosphate; D011451:Prostaglandin-Endoperoxide Synthases; D013110:Sphingosine; D002118:Calcium