L-cysteine/cystathionine-β-synthase-induced relaxation in mouse aorta involves L-serine/sphingosine-1-phosphate/nitric oxide axis.

BACKGROUND AND PURPOSE: Among the three enzymes involved in the transsulfuration pathway only cystathionine β-synthase (CBS) converts L-cysteine into L-serine and H2 S. L-serine is also involved in the de novo sphingolipid biosynthesis through a condensation with palmitoyl-CoA by the action of serine palmitoyltransferase (SPT). Here we have investigated if L-serine is involved in the vasorelaxant effect.

EXPERIMENTAL APPROACH: The presence of CBS in mice vascular endothelium was assessed by immunohistochemistry and immunofluorescence. The relaxant activity of L-serine (0.1 - 300 μM) and L-cysteine (0.1-300 μM) was estimated on mouse aorta rings in presence or in absence of endothelium. A pharmacological modulation study evaluated NO and sphingosine-1- phosphate (S1P) involvement. The NO and S1P levels were also measured following incubation of aorta tissue with either L-serine (1, 10, 100 μM) or L-cysteine (10, 100 μM, 1 mM).

KEY RESULTS: L-serine relaxed aorta rings in endothelium-dependent manner. The vascular effect was reduced by L-NAME and wortmaninn. A similar pattern was obtained with L-cysteine. The S1P1 receptor antagonist (W146) or the SPT inhibitor (myriocin) reduced either L-serine or L-cysteine relaxant effect. L-serine or L-cysteine incubation increased NO and S1P levels in mouse aorta.

CONCLUSION AND IMPLICATIONS: L-serine, a byproduct formed within the transsulfuration pathway starting from L-cysteine via CBS, contributes to the vasodilatory action of L-cysteine. The L-serine effect involves both NO and S1P. This mechanism could be involved in the marked dysregulation of vascular tone in hyperhomocysteinemic patients (CBS deficiency) and may represent a feasible therapeutic target.