title: Sphingosine-1-phosphate signalling-a key player in the pathogenesis of Angiotensin II-induced hypertension.
abstract: Hypertension is a complex condition involving functional and structural alterations of the microvasculature and an activation of the immune system. T-lymphocytes play a crucial role during the development of hypertension in experimental models, yet the underlying mechanisms remain elusive. Lymphocyte egress from lymph nodes is controlled by sphingosine-1-phosphate (S1P), a natural lipid mediator regulating immune cell and vascular function in health and disease. We therefore investigated the involvement of S1P signalling in the pathogenesis of hypertension.
  
  
  
  Angiotensin-II (AngII) treatment resulted in high blood pressure (BP) associated to increased plasma S1P and circulating T-cell counts. T-cell egress from lymph nodes was found to be a critical initial step for the onset of hypertension as fingolimod, a S1P-receptor agonist sequestering lymphocytes in the lymph nodes and inducing lymphopenia, blunted BP responses to AngII. Furthermore, activity of S1P-generating enzyme type 2 (SphK2) in haematopoietic cells critically contributed to AngII-induced lymphocyte mobilization from the lymph nodes as SphK2-/-mice and mice where SphK2 was ablated only in the haematopoietic system presented an accumulation of T-cells in mesenteric lymph nodes and a blunted BP response. In addition, deregulation of vascular SphK2 expression associated to a thrombo-inflammatory phenotype of the microvasculature, and to functional alterations of small resistance arteries.
  
  
  
  The presented results point to a critical involvement of S1P and its signalling axis in the pathogenesis of hypertension. Specifically, SphK2 evolves as key player in immune cell trafficking and vascular dysfunction contributing to the development of overt hypertension.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 161, Planta 6, 08036 Barcelona, Spain; anja.meissner@gmail.com anna.planas@iibb.csic.es.
authors.forename: Anja
authors.initials: A
authors.lastname: Meissner
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 161, Planta 6, 08036 Barcelona, Spain.|Departament d'Isquèmia Cerebral i Neurodegeneració, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Rosselló 161, Planta 6, 08036 Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Miro
authors.affiliation: Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, Edifici M, Avinguda de Can Domènech, Universitat Autònoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Jiménez-Altayó
authors.affiliation: Departament d'Isquèmia Cerebral i Neurodegeneració, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Rosselló 161, Planta 6, 08036 Barcelona, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Jurado
authors.affiliation: Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, Edifici M, Avinguda de Can Domènech, Universitat Autònoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vila
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 161, Planta 6, 08036 Barcelona, Spain; anja.meissner@gmail.com anna.planas@iibb.csic.es.|Departament d'Isquèmia Cerebral i Neurodegeneració, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Rosselló 161, Planta 6, 08036 Barcelona, Spain.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Planas
mesh_terms: D019264:Adoptive Transfer; D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism*; D008246:Lysophospholipids / Q000097:blood*; D008638:Mesenteric Arteries / Q000378:metabolism / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D013997:Time Factors; D066253:Vascular Remodeling; D000099157:Sphingosine Kinase
chemical_list: D000804:Angiotensin II; D000959:Antihypertensive Agents; D000068876:Fingolimod Hydrochloride; D018836:Inflammation Mediators; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; C060506:sphingosine 1-phosphate; C000603447:sphingosine kinase 2, mouse; D000099157:Sphingosine Kinase
keywords: Blood pressure; Endothelial dysfunction; Inflammation; Microvasculature; Sphingosine-1-phosphate (S1P)