title: The angiotensin II type 2 receptor activates flow-mediated outward remodelling through T cells-dependent interleukin-17 production.
abstract: The angiotensin II type 1 receptor (AT1R) through the activation of immune cells plays a key role in arterial inward remodelling and reduced blood flow in cardiovascular disorders. On the other side, flow (shear stress)-mediated outward remodelling (FMR), involved in collateral arteries growth in ischaemic diseases, allows revascularization. We hypothesized that the type 2 receptor (AT2R), described as opposing the effects of AT1R, could be involved in FMR.
  
  
  
  We studied FMR using a model of ligation of feed arteries supplying collateral pathways in the mouse mesenteric arterial bed in vivo. Seven days after ligation, diameter increased by 30% in high flow (HF) arteries compared with normal flow vessels. FMR was absent in mice lacking AT2R. At Day 2, T lymphocytes expressing AT2R were present preferentially around HF arteries. FMR did not occur in athymic (nude) mice lacking T cells and in mice treated with anti-CD3ε antibodies. AT2R activation induced interleukin-17 production by memory T cells. Treatment of nude mice or AT2R-deficient mice with interleukin-17 restored diameter enlargement in HF arteries. Interleukin-17 increased NO-dependent relaxation and matrix metalloproteinases activity, both important in FMR. Remodelling of feeding arteries in the skin flap model of ischaemia was also absent in AT2R-deficient mice and in anti-interleukin-17-treated mice. Finally, remodelling, absent in 12-month-old mice, was restored by a treatment with the AT2R non-peptidic agonist C21.
  
  
  
  AT2R-dependent interleukin-17 production by T lymphocyte is necessary for collateral artery growth and could represent a new therapeutic target in ischaemic disorders.
authors.affiliation: MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France UMR CNRS 6299, UMR INSERM 892, Angers University, F-49045 Angers, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Caillon
authors.affiliation: MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Grenier
authors.affiliation: MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France.
authors.forename: Linda
authors.initials: L
authors.lastname: Grimaud
authors.affiliation: MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France Cardiovascular Functions In Vitro (CARFI) Facility, Angers University, F-49045 Angers, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Vessieres
authors.affiliation: MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Guihot
authors.affiliation: UMR CNRS 6299, UMR INSERM 892, Angers University, F-49045 Angers, France Department of Immunology and Allergology, University Hospital, F-49045 Angers, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Blanchard
authors.affiliation: MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Lelievre
authors.affiliation: MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Chabbert
authors.affiliation: UMR CNRS 6299, UMR INSERM 892, Angers University, F-49045 Angers, France.
authors.forename: Etienne D
authors.initials: ED
authors.lastname: Foucher
authors.affiliation: UMR CNRS 6299, UMR INSERM 892, Angers University, F-49045 Angers, France Department of Immunology and Allergology, University Hospital, F-49045 Angers, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Jeannin
authors.affiliation: UMR CNRS 6299, UMR INSERM 892, Angers University, F-49045 Angers, France Department of Immunology and Allergology, University Hospital, F-49045 Angers, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Beauvillain
authors.affiliation: MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France Department of Vascular Medicine, University Hospital, F-49045 Angers, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Abraham
authors.affiliation: MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Loufrani
authors.affiliation: UMR CNRS 6299, UMR INSERM 892, Angers University, F-49045 Angers, France Department of Immunology and Allergology, University Hospital, F-49045 Angers, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Delneste
authors.affiliation: MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France Cardiovascular Functions In Vitro (CARFI) Facility, Angers University, F-49045 Angers, France Department of Vascular Medicine, University Hospital, F-49045 Angers, France daniel.henrion@inserm.fr.
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
mesh_terms: D000367:Age Factors; D000818:Animals; D062186:Arterial Pressure; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D003097:Collateral Circulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005838:Genotype; D020381:Interleukin-17 / Q000378:metabolism*; D007511:Ischemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008026:Ligation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008638:Mesenteric Arteries / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000601:surgery; D008643:Mesentery / Q000098:blood supply*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010641:Phenotype; D000067996:RAW 264.7 Cells; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012039:Regional Blood Flow; D012867:Skin / Q000098:blood supply*; D013152:Splanchnic Circulation / Q000187:drug effects; D013314:Stress, Mechanical; D013997:Time Factors; D066253:Vascular Remodeling; D014655:Vascular Resistance; D014664:Vasodilation
chemical_list: D020381:Interleukin-17; D044139:Receptor, Angiotensin, Type 2
keywords: Angiotensin II type 2 receptor; Blood flow; Collateral artery growth; Interleukin-17