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Examining the Role of Sphingosine Kinase-2 in the Regulation of Endothelial Cell Barrier Integrity. OBJECTIVE: A key mediator of vascular EC barrier integrity, S1P, is derived from phosphorylation of sphingosine by the SK-1 and SK-2. While previous work indicates that SK-1 can regulate EC barrier integrity, whether SK-2 has a similar role remains to be determined. METHODS: A cell impedance assay was used to assess human umbilical vein EC and bone marrow EC barrier integrity in vitro, with application of the SK inhibitors ABC294640, PF543, SKi, and MP-A08. In vivo studies were conducted using intravital microscopy to assess EC barrier integrity in SK-1 (Sphk1(-/-)) and SK-2 (Sphk2(-/-)) knock-out mice. RESULTS: Only ABC294640 and MP-A08, which can both inhibit SK-2, caused a decrease in EC barrier integrity in vitro in both cell types. Intravital microscopy revealed that Sphk1(-/-) mice had reduced EC barrier integrity compared to WT mice, whereas no change was evident in Sphk2(-/-) mice. CONCLUSIONS: Our data suggest that in vitro inhibition of SK-2, can compromise the integrity of the EC monolayer, while SK-1 exerts a more dominant control in vivo. These data may have clinical implications and could aid in the development of new treatments for disorders of vascular barrier function.