Sphingosine 1-phosphate induces endothelial nitric-oxide synthase activation through phosphorylation in human corpus cavernosum

Sphingosine 1-phosphate (S1P) is the natural ligand for a specific G protein-coupled receptors. In endothelial cells, S1P has been shown to modulate the activity of the endothelial nitricoxide synthase (eNOS) through phosphorylation operated by Akt. Nitric oxide (NO) produced by neuronal nitric-oxide synthase and eNOS plays a central role in triggering and maintaining penile erection. This study has assessed the possibility of a similar cross-talk between eNOS and S1P in human corpus cavernosum and whether this interaction is connected to penile vascular response. Quantitative reverse transcription-polymerase chain reaction demonstrated the presence of S1P 1, S1P 2, and S1P 3 receptors in both the human corpus cavernosum (HCC) and the penile artery. S1P on its own did not relax or contract HCC strips, but on the other hand, incubation with S1P (0.1 mu M) caused a 6-fold increase in relaxation induced by a subliminal dose of acetylcholine. This effect is dependent upon eNOS activation through an Akt-dependent phosphorylation, as demonstrated by pharmacological modulation with L-nitroarginine methyl ester and wortmannin and by Western blot studies. In human tissue, S1P seems to be the possible candidate for the activation of the eNOS calcium-independent pathway. This pathway may represent a new therapeutic area of intervention in erectile dysfunction (ED) to develop a way to selectively promote NO production at the endothelial level. This approach could also be used to enhance phosphodiesterase 5 therapy in patients with ED that are poor responders, such as in the case of diabetes.