Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice.
Sci Transl Med
; 5(183): 183ra58, 1-11, 2013 May 01.
Article
em En
| MEDLINE
| ID: mdl-23636094
ABSTRACT
Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4(SMKO)) leads to loss of the SMC contractile phenotype, hyperproliferation, and ascending aortic aneurysms. We report that abnormal up-regulation of angiotensin-converting enzyme (ACE) in SMCs and subsequent activation of angiotensin II (AngII) signaling are involved in the onset of aortic aneurysms in Fbln4(SMKO) mice. In this model, aneurysm formation was completely prevented by inhibition of the AngII pathway with losartan or captopril within a narrow therapeutic window during the first month of life, even though the altered mechanical properties of blood vessel walls were not reversed by the pharmacological treatment. The therapeutic effects of losartan in Fbln4(SMKO) mice do not require the AngII receptor type 2 (Agtr2) but likely require both type 1a (Agtr1a) and 1b (Agtr1b) receptors. The results indicate that fibulin-4 is a vascular matrix component required for regulation of local angiotensin signaling and development and maintenance of the SMC phenotype.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aorta
/
Aneurisma Aórtico
/
Angiotensina II
/
Transdução de Sinais
/
Proteínas da Matriz Extracelular
/
Peptidil Dipeptidase A
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Sci Transl Med
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2013
Tipo de documento:
Article