{"doi":"10.1161/circresaha.120.316711","title":"Endothelial S1P <sub>1</sub> Signaling Counteracts Infarct Expansion in Ischemic Stroke","abstract":"Rationale: 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 S1P 1 (S1P receptor-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 S1P 1 in the naive 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 endothelial cells. S1P 1 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 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, endothelial cell S1P 1 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 S1P 1 -selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion. 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 blood-brain barrier-penetrating S1P 1 agonists.","journal":"Circulation Research","year":2020,"id":51955,"datarank":0.7475409932562506,"base_score":4.983606621708336,"endowment":4.983606621708336,"self_citation_contribution":0.7475409932562506,"citation_network_contribution":0.0,"self_endowment_contribution":0.7475409932562506,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":145,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":261624,"name":"Marine Poittevin","orcid":null,"position":1,"is_corresponding":false},{"id":261625,"name":"Ammar Benarab","orcid":null,"position":2,"is_corresponding":false},{"id":260713,"name":"Philippe Bonnin","orcid":"0000-0003-3184-3740","position":3,"is_corresponding":false},{"id":260714,"name":"Giuseppe Faraco","orcid":"0000-0001-8675-4580","position":4,"is_corresponding":false},{"id":260715,"name":"Hiroki Uchida","orcid":"0009-0003-5650-1752","position":5,"is_corresponding":false},{"id":260716,"name":"Julie Favre","orcid":"0000-0003-1044-0950","position":6,"is_corresponding":false},{"id":260717,"name":"Lidia García‐Bonilla","orcid":"0000-0003-3832-0037","position":7,"is_corresponding":false},{"id":261626,"name":"Manuela CL Garcia","orcid":null,"position":8,"is_corresponding":false},{"id":260718,"name":"Pierre‐Louis Léger","orcid":"0000-0001-5234-9106","position":9,"is_corresponding":false},{"id":260719,"name":"Patrice Thérond","orcid":"0000-0002-7655-2229","position":10,"is_corresponding":false},{"id":260720,"name":"Thomas Mathivet","orcid":"0000-0001-7761-1684","position":11,"is_corresponding":false},{"id":261627,"name":"Gwennhaël Autret","orcid":null,"position":12,"is_corresponding":false},{"id":261628,"name":"Véronique Baudrie","orcid":null,"position":13,"is_corresponding":false},{"id":261629,"name":"Ludovic Couty","orcid":null,"position":14,"is_corresponding":false},{"id":260721,"name":"Mari Kono","orcid":"0000-0003-2447-4350","position":15,"is_corresponding":false},{"id":261630,"name":"Aline Chevallier","orcid":null,"position":16,"is_corresponding":false},{"id":260722,"name":"Hira Niazi","orcid":"0000-0003-4737-2613","position":17,"is_corresponding":false},{"id":260723,"name":"Pierre‐Louis Tharaux","orcid":"0000-0002-6062-5905","position":18,"is_corresponding":false},{"id":38374,"name":"Jerold Chun","orcid":"0000-0003-3964-0921","position":19,"is_corresponding":false},{"id":260724,"name":"Susan R. 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