TGFß (Transforming Growth Factor-ß) Blockade Induces a Human-Like Disease in a Nondissecting Mouse Model of Abdominal Aortic Aneurysm.
Arterioscler Thromb Vasc Biol
; 37(11): 2171-2181, 2017 11.
Article
em En
| MEDLINE
| ID: mdl-28912363
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 TGFß (transforming growth factor-ß) 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 ANDRESULTS:
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 TGFß 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. TGFß blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1ß or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1ß after disease initiation has no effect on AAA progression to rupture.CONCLUSIONS:
Endogenous TGFß activity is required for the healing of AAA. TGFß 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aorta Abdominal
/
Ruptura Aórtica
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Elastase Pancreática
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Fator de Crescimento Transformador beta
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Aneurisma da Aorta Abdominal
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Remodelação Vascular
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Anticorpos Monoclonais
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article