Endothelial S1P <sub>1</sub> Signaling Counteracts Infarct Expansion in Ischemic Stroke

DOI Web Site 3 Citations
  • 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.).
  • 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.).
  • 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.).
  • Philippe Bonnin
    Université de Paris, INSERM U965 and Physiologie Clinique - Explorations-Fonctionnelles, AP-HP, Hôpital Lariboisière, France (P.B., N.K.).
  • Giuseppe Faraco
    Feil Family Brain and Mind Research Institute (G.F., L.G.-B., C.I.), Weill Cornell Medical College, Cornell University, New York.
  • Hiroki Uchida
    Center for Vascular Biology (H.U., T.S.), Weill Cornell Medical College, Cornell University, New York.
  • Julie Favre
    MITOVASC Institute, CARFI Facility, CNRS UMR 6015, INSERM U1083, Angers University, France (J.F., M.C.L.G., D.H.).
  • 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.
  • Manuela C.L. Garcia
    MITOVASC Institute, CARFI Facility, CNRS UMR 6015, INSERM U1083, Angers University, France (J.F., M.C.L.G., D.H.).
  • Pierre-Louis Léger
    Institut des Vaisseaux et du Sang, Hôpital Lariboisière, France (M.P., P.-L.L.).
  • Patrice Thérond
    Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Biochimie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France (P.T.).
  • 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.).
  • 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.).
  • 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.).
  • 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.).
  • 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.).
  • Aline Chevallier
  • 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.).
  • 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.).
  • Jerold Chun
    Neuroscience Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA (J.C.).
  • Susan R. Schwab
    Skirball Institute of Biomolecular Medicine, New York University School of Medicine, NY (S.R.S.).
  • 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.).
  • 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.).
  • 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.).
  • Christiane Charriaut-Marlangue
    INSERM U1141, Hôpital Robert Debré (P.-L.L., C.C.-M.).
  • Teresa Sanchez
    Center for Vascular Biology (H.U., T.S.), Weill Cornell Medical College, Cornell University, New York.
  • Nathalie Kubis
    Université de Paris, INSERM U965 and Physiologie Clinique - Explorations-Fonctionnelles, AP-HP, Hôpital Lariboisière, France (P.B., N.K.).
  • Daniel Henrion
    MITOVASC Institute, CARFI Facility, CNRS UMR 6015, INSERM U1083, Angers University, France (J.F., M.C.L.G., D.H.).
  • Costantino Iadecola
    Feil Family Brain and Mind Research Institute (G.F., L.G.-B., C.I.), Weill Cornell Medical College, Cornell University, New York.
  • Timothy Hla
    Vascular Biology Program, Boston Children’s Hospital, MA (T.H.).
  • 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.).

Abstract

<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>

Journal

  • Circulation Research

    Circulation Research 128 (3), 363-382, 2021-02-05

    Ovid Technologies (Wolters Kluwer Health)

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