Fabien Lareyre1, Marc Clément1, Juliette Raffort1, Stefanie Pohlod1, Meghana Patel1, Bruno Esposito1, Leanne Master1, Alison Finigan1, Marie Vandestienne1, Nikolaos Stergiopulos1, Soraya Taleb1, Bram Trachet1, Ziad Mallat2. 1. From the Division of Cardiovascular Medicine, University of Cambridge, UK (F.L., M.C., J.R., M.P., L.M., A.F., Z.M.); Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale, Institute for Research on Cancer and Aging in Nice, France (F.L., J.R.); University Hospital of Nice, France (F.L, J.R.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, France (B.E., M.V., S.T., Z.M.); Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Switzerland (S.P., N.S., B.T.); and IBiTech-bioMMeda (Institute Biomedical Technology-Biofluid, Tissue and Solid Mechanics for Medical Applications), Ghent University, Belgium (N.S., B.T.). 2. From the Division of Cardiovascular Medicine, University of Cambridge, UK (F.L., M.C., J.R., M.P., L.M., A.F., Z.M.); Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale, Institute for Research on Cancer and Aging in Nice, France (F.L., J.R.); University Hospital of Nice, France (F.L, J.R.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, France (B.E., M.V., S.T., Z.M.); Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Switzerland (S.P., N.S., B.T.); and IBiTech-bioMMeda (Institute Biomedical Technology-Biofluid, Tissue and Solid Mechanics for Medical Applications), Ghent University, Belgium (N.S., B.T.). zm255@medchl.cam.ac.uk.
Abstract
OBJECTIVE: Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFβ (transforming growth factor-β) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. APPROACH AND RESULTS: Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGFβ using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGFβ blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1β or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1β after disease initiation has no effect on AAA progression to rupture. CONCLUSIONS: Endogenous TGFβ activity is required for the healing of AAA. TGFβ blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets.
OBJECTIVE: Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFβ (transforming growth factor-β) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. APPROACH AND RESULTS: Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGFβ using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGFβ blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1β or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1β after disease initiation has no effect on AAA progression to rupture. CONCLUSIONS: Endogenous TGFβ activity is required for the healing of AAA. TGFβ blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets.
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
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