Aortopathy in a Mouse Model of Marfan Syndrome Is Not Mediated by Altered Transforming Growth Factor ß Signaling.
J Am Heart Assoc
; 6(1)2017 01 24.
Article
em En
| MEDLINE
| ID: mdl-28119285
ABSTRACT
BACKGROUND:
Marfan syndrome (MFS) is caused by mutations in the gene encoding fibrillin-1 (FBN1); however, the mechanisms through which fibrillin-1 deficiency causes MFS-associated aortopathy are uncertain. Recently, attention was focused on the hypothesis that MFS-associated aortopathy is caused by increased transforming growth factor-ß (TGF-ß) signaling in aortic medial smooth muscle cells (SMC). However, there are many reasons to doubt that TGF-ß signaling drives MFS-associated aortopathy. We used a mouse model to test whether SMC TGF-ß signaling is perturbed by a fibrillin-1 variant that causes MFS and whether blockade of SMC TGF-ß signaling prevents MFS-associated aortopathy. METHODS ANDRESULTS:
MFS mice (Fbn1C1039G/+ genotype) were genetically modified to allow postnatal SMC-specific deletion of the type II TGF-ß receptor (TBRII; essential for physiologic TGF-ß signaling). In young MFS mice with and without superimposed deletion of SMC-TBRII, we measured aortic dimensions, histopathology, activation of aortic SMC TGF-ß signaling pathways, and changes in aortic SMC gene expression. Young Fbn1C1039G/+ mice had ascending aortic dilation and significant disruption of aortic medial architecture. Both aortic dilation and disrupted medial architecture were exacerbated by superimposed deletion of TBRII. TGF-ß signaling was unaltered in aortic SMC of young MFS mice; however, SMC-specific deletion of TBRII in Fbn1C1039G/+ mice significantly decreased activation of SMC TGF-ß signaling pathways.CONCLUSIONS:
In young Fbn1C1039G/+ mice, aortopathy develops in the absence of detectable alterations in SMC TGF-ß signaling. Loss of physiologic SMC TGF-ß signaling exacerbates MFS-associated aortopathy. Our data support a protective role for SMC TGF-ß signaling during early development of MFS-associated aortopathy.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aorta
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Fator de Crescimento Transformador beta
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Proteínas Serina-Treonina Quinases
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Aneurisma da Aorta Torácica
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Receptores de Fatores de Crescimento Transformadores beta
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Fibrilina-1
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Síndrome de Marfan
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article