Endothelial S1P 1 Signaling Counteracts Infarct Expansion in Ischemic Stroke-Reference-Cited by-同舟云学术

Endothelial S1P 1 Signaling Counteracts Infarct Expansion in Ischemic Stroke

Published:2021-02-05 Issue:3 Volume:128 Page:363-382
ISSN:0009-7330
Container-title:Circulation Research
language:en
Short-container-title:Circ Res

Author:

Nitzsche Anja¹^ORCID,Poittevin Marine¹²,Benarab Ammar¹,Bonnin Philippe³^ORCID,Faraco Giuseppe⁴^ORCID,Uchida Hiroki⁵,Favre Julie⁶,Garcia-Bonilla Lidia⁴,Garcia Manuela C.L.⁶,Léger Pierre-Louis²⁷,Thérond Patrice⁸⁹¹⁰,Mathivet Thomas¹^ORCID,Autret Gwennhael¹^ORCID,Baudrie Véronique¹,Couty Ludovic¹,Kono Mari¹¹^ORCID,Chevallier Aline,Niazi Hira¹^ORCID,Tharaux Pierre-Louis¹^ORCID,Chun Jerold¹²,Schwab Susan R.¹³,Eichmann Anne¹,Tavitian Bertrand¹^ORCID,Proia Richard L.¹¹,Charriaut-Marlangue Christiane⁷^ORCID,Sanchez Teresa⁵^ORCID,Kubis Nathalie³¹⁴,Henrion Daniel⁶^ORCID,Iadecola Costantino⁴^ORCID,Hla Timothy¹⁵^ORCID,Camerer Eric¹^ORCID

Affiliation:

1. 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.).

2. Institut des Vaisseaux et du Sang, Hôpital Lariboisière, France (M.P., P.-L.L.).

3. Université de Paris, INSERM U965 and Physiologie Clinique - Explorations-Fonctionnelles, AP-HP, Hôpital Lariboisière, France (P.B., N.K.).

4. Feil Family Brain and Mind Research Institute (G.F., L.G.-B., C.I.), Weill Cornell Medical College, Cornell University, New York.

5. Center for Vascular Biology (H.U., T.S.), Weill Cornell Medical College, Cornell University, New York.

6. MITOVASC Institute, CARFI Facility, CNRS UMR 6015, INSERM U1083, Angers University, France (J.F., M.C.L.G., D.H.).

7. INSERM U1141, Hôpital Robert Debré (P.-L.L., C.C.-M.).

8. Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Biochimie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France (P.T.).

9. Université Paris-Sud, France (P.T.).

10. UFR de Pharmacie, EA 4529, Châtenay-Malabry, France (P.T.).

11. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Institutes of Health, Bethesda, MD, USA (M.K., R.L.P.).

12. Neuroscience Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA (J.C.).

13. Skirball Institute of Biomolecular Medicine, New York University School of Medicine, NY (S.R.S.).

14. Université de Paris, INSERM U1148, Hôpital Bichat, France (N.K.).

15. Vascular Biology Program, Boston Children’s Hospital, MA (T.H.).

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.

Funder

Fondation Leducq

Fondation pour la Recherche Médicale

Agence Nationale de la Recherche

Fondation de France

Fondation Lefoulon Delalande

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

Reference82 articles.