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TGFβ (Transforming Growth Factor-β) Blockade Induces a Human-Like Disease in a Nondissecting Mouse Model of Abdominal Aortic Aneurysm.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Lareyre, Fabien 
Clément, Marc 
Raffort, Juliette 
Pohlod, Stefanie 
Patel, Meghana 

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.

Description

Keywords

aneurysm, animals, humans, immune system, models, Animals, Antibodies, Monoclonal, Aorta, Abdominal, Aortic Aneurysm, Abdominal, Aortic Rupture, Apolipoproteins E, Chemotaxis, Leukocyte, Dilatation, Pathologic, Disease Models, Animal, Disease Progression, Extracellular Matrix, Interleukin-1beta, Kinetics, Male, Mice, Inbred C57BL, Mice, Knockout, Pancreatic Elastase, Synchrotrons, Thrombosis, Transforming Growth Factor beta, Ultrasonography, Vascular Remodeling, Wound Healing

Journal Title

Arterioscler Thromb Vasc Biol

Conference Name

Journal ISSN

1079-5642
1524-4636

Volume Title

37

Publisher

Ovid Technologies (Wolters Kluwer Health)
Sponsorship
British Heart Foundation (RG/15/11/31593)