In synthesis, these findings suggest that in the context of preconditioning and stroke, the signaling between SphK2 and its products fingolimod phosphate or S1P is bidirectional with an induction of SphK2 following preconditioning stimuli and a lost efficacy of HIF-stabilizing factors in SphK2-deficient mice on the one hand and a HIF-dependency of the preconditioning effect of fingolimod on the other hand. Here, SPHK2 is linked to stroke disorder.