Endothelial S1P₁ Signaling Counteracts Infarct Expansion in Ischemic Stroke.

Abstract

Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P₁ (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P₁ also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P₁ modulation in stroke. To address roles and mechanisms of engagement of endothelial cell S1P₁ in the naive 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 S1P₁ in the mouse brain. With an S1P₁ signaling reporter, we reveal that abluminal polarization shields S1P₁ from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P₁ signaling sustains hallmark endothelial functions in the naive brain and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by endothelial cell-selective deficiency in S1P production, export, or the S1P₁ receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P₁ provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P₁ supports blood-brain barrier function, microvascular patency, and the rerouting of blood to hypoperfused brain tissue through collateral anastomoses. Boosting these functions by supplemental pharmacological engagement of the endothelial receptor pool with a blood-brain barrier penetrating S1P₁-selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion. 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 blood-brain barrier-penetrating S1P₁ agonists.