Methods for stimulating cerebrovascular function

As critical regulators of blood-brain barrier (BBB) function and tissue perfusion, endothelial cells are vital for cerebrovascular function and adaptation to stress and thus for brain health. Stimulation or normalization of cerebrovascular function may improve outcome of both acute and chronic central nervous system disorders. The circulating lipid mediator sphingosine1-phosphate (S1P) sustains both EC functions and lymphocyte egress through the S1P1 receptor in other organs. The inventors report that EC S1P1 signaling is also essential for cerebral blood flow, BBB function, and anti-inflammatory properties of the brain endothelium in naïve mice, and that signaling expands during ischemia. Importantly, endothelial S1P1 is polarized to the abluminal surface of most brain endothelial cells, shielding the receptor from circulating endogenous and synthetic ligands in the mature brain. As a consequence, endothelial cell autonomous S1P provision is required to sustain endothelial S1P1 signaling and endothelial function in ischemic stroke, and BBB-penetration is required for S1P1 agonists to engage the receptor at the BBB. Targeting of S1P1 with selective BBB-penetrating agonists was shown to limit cortical infarct expansion with or without reperfusion when applied up to 6 hours after MCA occlusion. Thus, the present invention relates to methods for stimulating cerebrovascular function in patients suffering from ischemic stroke, intracerebral hemorrhage, or central nervous system disorders associated with cerebrovascular dysfunction

Keywords: Stroke, Reperfusion, Blood-brain barrier, vascular, S1P1, cerebrovascular function, reperfusion
Patent Application number: PCT/EP2021/051140
Publications:
Circ Res. 2021 Feb 5;128(3):363-382. doi: 10.1161/CIRCRESAHA.120.316711. Epub 2020 Dec 2.

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