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

Abstract : Aims 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. Methods and results 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-CD31 anti-bodies. 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. Conclusion AT2R-dependent interleukin-17 production by T lymphocyte is necessary for collateral artery growth and could represent a new therapeutic target in ischaemic disorders.
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Cardiovascular Research, Oxford University Press (OUP), 2016, 112 (1), pp.515 - 525. 〈10.1093/cvr/cvw172〉
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Antoine Caillon, Céline Grenier, Linda Grimaud, Emilie Vessieres, Anne-Laure Guihot, et al.. The angiotensin II type 2 receptor activates flow-mediated outward remodelling through T cells-dependent interleukin-17 production. Cardiovascular Research, Oxford University Press (OUP), 2016, 112 (1), pp.515 - 525. 〈10.1093/cvr/cvw172〉. 〈inserm-01382460〉

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