Abstract 12272: Sphingosine-1-phosphate Reverts the Mechanism of Flow Induced Dilation to Nitric Oxide in Diseased Human Arterioles

Abstract

Impairment of flow-induced dilation (FID; the ability of the vasculature to dilate to increased shear stress in an endothelium-dependent manner) is predictive for future cardiovascular events. Recent discoveries in our laboratory have shown that increases in ceramide, through inhibiting its catabolism or exogenous administration, transitions the mediator of FID from NO to mitochondrial-derived H2O2, the same transition that occurs between health and disease. Ceramide can also undergo transformation to sphingosine, the backbone of all sphingolipids, and eventually phosphorylated to sphingosine-1-phosphate (S1P), known to have beneficial effects within the endothelial cell. We tested the hypothesis that exogenous administration of S1P will revert the mediator of FID back to NO in vessels from patients with CAD. Small adipose arterioles (100-200μm) from patients with CAD were prepared for videomicroscopy and constricted with endothelin-1. Changes in internal diameter to flow were recorded. The presence of PEG-Catalase (500U/ml) did not affect FID in CAD arterioles pre-treated with S1P (1μM, 16-20hrs) (82.4%±5.4 of maximal dilator capacity, n=7) compared to control (81.7%±2.9, n=4), however dilation was significantly impaired in the presence of L-NAME (100μM) (0.3%±2.0, n=8, p<0.01, one-way ANOVA). Dilation with S1P alone was no different from control (80.6%±3.8, n=8, versus 81.7%±2.9, n=4, respectively). Together these data suggest that S1P is critical in regulating the mediator of FID and promotes vasodilation through the NO pathway as opposed to H2O2. We conclude that the ceramide-sphinogsine-S1P balance has a significant influence in determining the primary mediator of FID.