Antoine Caillon1, Céline Grenier2, Linda Grimaud2, Emilie Vessieres3, Anne-Laure Guihot2, Simon Blanchard4, Eric Lelievre2, Marie Chabbert2, Etienne D Foucher5, Pascale Jeannin4, Céline Beauvillain4, Pierre Abraham6, Laurent Loufrani2, Yves Delneste4, Daniel Henrion7. 1. 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. 2. MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France. 3. 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. 4. UMR CNRS 6299, UMR INSERM 892, Angers University, F-49045 Angers, France Department of Immunology and Allergology, University Hospital, F-49045 Angers, France. 5. UMR CNRS 6299, UMR INSERM 892, Angers University, F-49045 Angers, France. 6. MITOVASC Institute, UMR CNRS 6214, INSERM U1083, Angers University, F-49045 Angers, France Department of Vascular Medicine, University Hospital, F-49045 Angers, France. 7. 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.
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-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. 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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-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. 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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