Nitzsche A, Poittevin M, Benarab A, et al. - Vascular functions in other organs are coordinated by sphingosine 1-phosphate (S1P) signaling, and S1P receptor-1 (S1P₁) modulators, like fingolimod, are promising for the treatment of ischemic and hemorrhagic stroke. S1P₁ also coordinates trafficking of lymphocytes, which are currently considered a key therapeutic target for S1P₁ modulation in stroke, so researchers sought to assess functions and mechanisms of engagement of endothelial cell S1P₁ in the naïve and ischemic brain and it’s potential as a target for cerebrovascular therapy. A critical vascular protective role for endothelial S1P₁ in the mouse brain was seen using spatial modulation of S1P provision and signaling. This research provides genetic evidence to support the endothelium's crucial role in maintaining the ischemic penumbra's perfusion and microvascular patency that is coordinated by S1P signaling and can be harnessed with blood-brain barrier-penetrating S1P₁ agonists for neuroprotection.