S1P (Sphingosine-1-Phosphate)-Induced Vasodilation in Human Resistance Arterioles During Health and Disease

Preclinical studies suggest that S1P (sphingosine-1-phosphate) influences blood pressure regulation primarily through NO-induced vasodilation. Because microvascular tone significantly contributes to mean arterial pressure, the mechanism of S1P on human resistance arterioles was investigated. We hypothesized that S1P induces NO-mediated vasodilation in human arterioles from adults without coronary artery disease (non-coronary artery disease) through activation of 2 receptors, S1PR₁ (S1P receptor 1) and S1PR₃ (S1P receptor 3). Furthermore, we tested whether this mechanism is altered in vessels from patients diagnosed with coronary artery disease.

Human arterioles (50-200 µm in luminal diameter) were dissected from otherwise discarded surgical adipose tissue, cannulated, and pressurized. Following equilibration, resistance vessels were preconstricted with ET-1 (endothelin-1) and changes in internal diameter to increasing concentrations of S1P (10-12 to 10-7 M) in the presence or absence of various inhibitors were measured.

S1P resulted in significant dilation that was abolished in vessels treated with S1PR₁ and S1PR₃ inhibitors and in vessels with reduced expression of each receptor. Dilation to S1P was significantly reduced in the presence of the NOS (NO synthase) inhibitor Nω-nitro-L-arginine methyl ester and the NO scavenger 2-4-(carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. Interestingly, dilation was also significantly impaired in the presence of PEG-catalase (polyethylene glycol-catalase), apocynin, and specific inhibitors of NOX (NADPH oxidases) 2 and 4. Dilation in vessels from patients diagnosed with coronary artery disease was dependent on H₂O₂ alone which was only dependent on S1PR₃ activation.

These translational studies highlight the inter-species variation observed in vascular signaling and provide insight into the mechanism by which S1P regulates microvascular resistance and ultimately blood pressure in humans.