Endothelial S1P1 Signaling Counteracts Infarct Expansion in Ischemic Stroke.
Anja Nitzsche1, Marine Poittevin1,2, Ammar Benarab1
1Université de Paris, Paris Cardiovascular Research Centre, INSERM U970, France (A.N., M.P., A.B., T.M., G.A., V.B., L.C., A.C., H.N., P.-L.T., A.E., B.T., E.C.).
Circulation Research
|December 10, 2020
Summary
Endothelial Sphingosine 1-phosphate receptor-1 (S1P1) signaling is crucial for brain blood vessel health and stroke recovery. Targeting this pathway in brain endothelial cells offers a novel neuroprotection strategy for ischemic stroke.
Area of Science:
- Neuroscience
- Vascular Biology
- Pharmacology
Background:
- Cerebrovascular function is vital for brain health, with endogenous protective pathways offering therapeutic potential for neurological disorders.
- Sphingosine 1-phosphate (S1P) signaling regulates vascular functions, and S1P receptor-1 (S1P1) modulators show promise for stroke treatment.
- Current stroke therapy strategies for S1P1 primarily target lymphocytes, overlooking endothelial roles.
Purpose of the Study:
- To investigate the role and mechanisms of endothelial S1P1 in the naive and ischemic brain.
- To evaluate endothelial S1P1 as a potential target for cerebrovascular therapy in stroke.
Main Methods:
- Utilized spatial modulation of S1P provision and signaling in mouse models.
- Employed an S1P1 signaling reporter to map receptor activity.
- Generated endothelial cell-specific deficiencies in S1P production, export, or S1P1 receptor.
Main Results:
- Demonstrated a critical vascular protective role for endothelial S1P1 in the mouse brain.
- Revealed abluminal polarization of S1P1 in mature blood-neural barrier, restricting signaling to specific arteriolar endothelial cells.
- Showed that disrupting endothelial S1P1 pathways exacerbates stroke injury, while lymphopenia offers only modest protection.
Conclusions:
- Provided genetic evidence for the endothelium's pivotal role in maintaining perfusion and microvascular patency in the ischemic penumbra.
- Highlighted S1P signaling as a key coordinator of these endothelial functions.
- Indicated that blood-brain barrier-penetrating S1P1 agonists can be harnessed for neuroprotection by targeting endothelial S1P1.
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