Endothelial S1P Signaling Counteracts Infarct Expansion in Ischemic Stroke.

Cerebrovascular function is critical for brain health, and endogenous vascular-protective pathways may provide therapeutic targets for neurological disorders. Sphingosine 1-phosphate (S1P) signaling coordinates vascular functions in other organs, and S1P receptor-1 (S1P) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P modulation in stroke. To address roles and mechanisms of engagement of endothelial cell (EC) S1P in the naïve and ischemic brain and its potential as a target for cerebrovascular therapy. Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P in the mouse brain. With an S1P signaling reporter, we reveal that abluminal polarization shields S1P from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar ECs. S1P signaling sustains hallmark endothelial functions in the naïve brain, and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by EC-selective deficiency in S1P production, export, or the S1P receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P provides modest protection only in the context of reperfusion. In the ischemic brain, EC S1P supports blood-brain barrier (BBB) function, microvascular patency, and the rerouting of blood to hypo-perfused brain tissue through collateral anastomoses. Selective S1P agonism counteracts cortical infarct expansion after middle cerebral artery occlusion by engaging the endothelial receptor pool after BBB penetration. This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with BBB-penetrating S1P agonists.