cannabidiol and sphingosine-1-phosphate

The endothelium-dependent mesenteric vasorelaxant effect of anandamide has been attributed to stimulation of a Gi/Go-coupled receptor, for which the nonpsychoactive analog abnormal cannabidiol (abn-cbd, (-)-4-(3-3,4-trans-p-menthadien-[1,8]-yl)olivetol) is a selective agonist and the compound O-1918 ((-)-4-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol) is a selective antagonist. In human umbilical vein endothelial cells abn-cbd was reported to increase the phosphorylation of p44/42 mitogen activated protein kinase (MAPK) and protein kinase B/Akt, and these effects could be inhibited by pertussis toxin, by phosphatidylinositol 3-kinase (PI3K) inhibitors or by O-1918 [Mol. Pharmacol. 63 (2003) 699]. In the present experiments, abn-cbd caused a concentration-dependent increase in human umbilical vein endothelial cell migration, as quantified in a transwell chamber. This effect was antagonized by O-1918, by the PI3K inhibitor wortmannin, and by pertussis toxin, but not by the cannabinoid CB1 receptor antagonist AM251 or the cannabinoid CB2 receptor antagonist SR144528. The EDG-1 receptor agonist sphingosine-1-phosphate also increased human umbilical vein endothelial cell migration, but this response was unaffected by O-1918. In Chinese hamster ovary cells stably transfected with the gene encoding the EDG-1 receptor, p44/42 MAPK phosphorylation was unaffected by abn-cbd, but strongly induced by sphingosine-1-phosphate. These results indicate that an abn-cbd-sensitive endothelial receptor distinct from cannabinoid CB1, CB2 or EDG-1 receptors mediates not only vasorelaxation but also endothelial cell migration.

Topics: Androstadienes; Animals; Blotting, Western; Cannabidiol; Cell Movement; Cells, Cultured; CHO Cells; Cricetinae; Endothelial Cells; Enzyme Inhibitors; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Indicators and Reagents; Lysophospholipids; Mitogen-Activated Protein Kinase 1; Pertussis Toxin; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Estrogen; Receptors, G-Protein-Coupled; Receptors, Lysosphingolipid; Resorcinols; Sphingosine; Sphingosine-1-Phosphate Receptors; Umbilical Veins; Wortmannin