The angiotensin II type 2 receptor activates flow-mediated outward remodelling through T cells-dependent interleukin-17 production

• Published in: Cardiovascular research 2016-10, Vol.112 (1), p.515-525
• Main Authors: Caillon, Antoine, Grenier, Céline, Grimaud, Linda, Vessieres, Emilie, Guihot, Anne-Laure, Blanchard, Simon, Lelievre, Eric, Chabbert, Marie, Foucher, Etienne D, Jeannin, Pascale, Beauvillain, Céline, Abraham, Pierre, Loufrani, Laurent, Delneste, Yves, Henrion, Daniel
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Arterial Pressure; Cancer; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Collateral Circulation; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Genotype; Interleukin-17 - metabolism; Ischemia - genetics; Ischemia - immunology; Ischemia - metabolism; Ischemia - physiopathology; Life Sciences; Ligation; Macrophages - drug effects; Macrophages - metabolism; Mechanotransduction, Cellular - drug effects; Mesenteric Arteries - drug effects; Mesenteric Arteries - immunology; Mesenteric Arteries - metabolism; Mesenteric Arteries - surgery; Mesentery - blood supply; Mice; Mice, Knockout; Mice, Nude; Phenotype; RAW 264.7 Cells; Receptor, Angiotensin, Type 2 - agonists; Receptor, Angiotensin, Type 2 - deficiency; Receptor, Angiotensin, Type 2 - genetics; Receptor, Angiotensin, Type 2 - metabolism; Regional Blood Flow; Skin - blood supply; Splanchnic Circulation - drug effects; Stress, Mechanical; Time Factors; Vascular Remodeling; Vascular Resistance; Vasodilation
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvw172

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.