Rationale:
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
1
) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P
1
also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P
1
modulation in stroke.
Objective:
To address roles and mechanisms of engagement of endothelial cell (EC) S1P
1
in the naïve and ischemic brain and its potential as a target for cerebrovascular therapy.
Methods and Results:
Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P
1
in the mouse brain. With an S1P
1
signaling reporter, we reveal that abluminal polarization shields S1P
1
from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar ECs. S1P
1
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
1
receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P
1
provides modest protection only in the context of reperfusion. In the ischemic brain, EC S1P
1
supports blood-brain barrier (BBB) function, microvascular patency, and the rerouting of blood to hypo-perfused brain tissue through collateral anastomoses. Selective S1P
1
agonism counteracts cortical infarct expansion after middle cerebral artery occlusion by engaging the endothelial receptor pool after BBB penetration.
Conclusions:
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
1
agonists.