Activation transcription factor-4 induced by fibroblast growth factor-2 regulates vascular endothelial growth factor-A transcription in vascular smooth muscle cells and mediates intimal thickening in rat arteries following balloon injury.
Circ Res
; 103(4): 378-87, 2008 Aug 15.
Article
en En
| MEDLINE
| ID: mdl-18617696
Activation transcription factor (ATF)-4 is a member of the ATF/CREB family of basic leucine zipper transcription factors that regulates cellular responses to a variety of stresses. The role of ATF-4 in smooth muscle cells of the vessel wall is completely unknown. Here, we show that ATF-4 expression is induced in smooth muscle cells in response to injury, both in vitro using a model of mechanical injury and in the media of balloon-injured rat carotid arteries. We demonstrate that ATF-4 is activated by fibroblast growth factor (FGF)-2, an injury-induced mitogen, through the phosphatidylinositol 3-kinase pathway. Injury also activates vascular endothelial growth factor (VEGF)-A, whose expression is stimulated by ATF-4 overexpression and exposure to FGF-2. FGF-2 induces ATF-4 binding to a recognition element located in the VEGF-A gene at +1767 bp and luciferase reporter gene expression dependent on this site. Moreover, ATF-4 knockdown with small interfering RNA or ATF-4 deficiency ameliorates FGF-2-inducible VEGF-A expression. Intraluminal delivery of ATF-4 small interfering RNA in rat carotid arteries blocks balloon injury-inducible ATF-4 and VEGF-A expression after 4 hours and intimal thickening after 14 days. These findings reveal, for the first time, the induction of ATF-4 by both vascular injury and FGF-2. ATF-4 serves as a conduit for the inducible expression of 1 growth factor by another during the process of intimal thickening.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Endotelio Vascular
/
Cateterismo
/
Factor 2 de Crecimiento de Fibroblastos
/
Túnica Íntima
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Factor A de Crecimiento Endotelial Vascular
/
Factor de Transcripción Activador 4
/
Músculo Liso Vascular
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Circ Res
Año:
2008
Tipo del documento:
Article
País de afiliación:
Australia
Pais de publicación:
Estados Unidos