Endothelial S1P <sub>1</sub> Signaling Counteracts Infarct Expansion in Ischemic Stroke
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- Anja Nitzsche
- Université 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.).
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- Marine Poittevin
- Université 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.).
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- Ammar Benarab
- Université 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.).
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- Philippe Bonnin
- Université de Paris, INSERM U965 and Physiologie Clinique - Explorations-Fonctionnelles, AP-HP, Hôpital Lariboisière, France (P.B., N.K.).
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- Giuseppe Faraco
- Feil Family Brain and Mind Research Institute (G.F., L.G.-B., C.I.), Weill Cornell Medical College, Cornell University, New York.
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- Hiroki Uchida
- Center for Vascular Biology (H.U., T.S.), Weill Cornell Medical College, Cornell University, New York.
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- Julie Favre
- MITOVASC Institute, CARFI Facility, CNRS UMR 6015, INSERM U1083, Angers University, France (J.F., M.C.L.G., D.H.).
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- Lidia Garcia-Bonilla
- Feil Family Brain and Mind Research Institute (G.F., L.G.-B., C.I.), Weill Cornell Medical College, Cornell University, New York.
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- Manuela C.L. Garcia
- MITOVASC Institute, CARFI Facility, CNRS UMR 6015, INSERM U1083, Angers University, France (J.F., M.C.L.G., D.H.).
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- Pierre-Louis Léger
- Institut des Vaisseaux et du Sang, Hôpital Lariboisière, France (M.P., P.-L.L.).
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- Patrice Thérond
- Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Biochimie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France (P.T.).
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- Thomas Mathivet
- Université 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.).
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- Gwennhael Autret
- Université 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.).
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- Véronique Baudrie
- Université 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.).
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- Ludovic Couty
- Université 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.).
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- Mari Kono
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Institutes of Health, Bethesda, MD, USA (M.K., R.L.P.).
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- Hira Niazi
- Université 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.).
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- Pierre-Louis Tharaux
- Université 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.).
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- Jerold Chun
- Neuroscience Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA (J.C.).
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- Susan R. Schwab
- Skirball Institute of Biomolecular Medicine, New York University School of Medicine, NY (S.R.S.).
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- Anne Eichmann
- Université 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.).
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- Bertrand Tavitian
- Université 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.).
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- Richard L. Proia
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Institutes of Health, Bethesda, MD, USA (M.K., R.L.P.).
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- Christiane Charriaut-Marlangue
- INSERM U1141, Hôpital Robert Debré (P.-L.L., C.C.-M.).
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- Teresa Sanchez
- Center for Vascular Biology (H.U., T.S.), Weill Cornell Medical College, Cornell University, New York.
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- Nathalie Kubis
- Université de Paris, INSERM U965 and Physiologie Clinique - Explorations-Fonctionnelles, AP-HP, Hôpital Lariboisière, France (P.B., N.K.).
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- Daniel Henrion
- MITOVASC Institute, CARFI Facility, CNRS UMR 6015, INSERM U1083, Angers University, France (J.F., M.C.L.G., D.H.).
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- Costantino Iadecola
- Feil Family Brain and Mind Research Institute (G.F., L.G.-B., C.I.), Weill Cornell Medical College, Cornell University, New York.
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- Timothy Hla
- Vascular Biology Program, Boston Children’s Hospital, MA (T.H.).
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- Eric Camerer
- Université 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.).
抄録
<jats:sec> <jats:title>Rationale:</jats:title> <jats:p> 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 <jats:sub>1</jats:sub> (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P <jats:sub>1</jats:sub> also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P <jats:sub>1</jats:sub> modulation in stroke. </jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p> To address roles and mechanisms of engagement of endothelial cell S1P <jats:sub>1</jats:sub> in the naive and ischemic brain and its potential as a target for cerebrovascular therapy. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results:</jats:title> <jats:p> Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P <jats:sub>1</jats:sub> in the mouse brain. With an S1P <jats:sub>1</jats:sub> signaling reporter, we reveal that abluminal polarization shields S1P <jats:sub>1</jats:sub> from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P <jats:sub>1</jats:sub> 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 <jats:sub>1</jats:sub> receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P <jats:sub>1</jats:sub> provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P <jats:sub>1</jats:sub> 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 <jats:sub>1</jats:sub> -selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p> 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 <jats:sub>1</jats:sub> agonists. </jats:p> </jats:sec>
収録刊行物
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- Circulation Research
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Circulation Research 128 (3), 363-382, 2021-02-05
Ovid Technologies (Wolters Kluwer Health)