RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Malabanan, KP  Kanellakis, P  Bobik, A  Khachigian, LM 
Citation: Malabanan KP, etal., Circ Res. 2008 Aug 15;103(4):378-87. doi: 10.1161/CIRCRESAHA.107.168682. Epub 2008 Jul 10.
RGD ID: 7421597
Pubmed: PMID:18617696   (View Abstract at PubMed)
DOI: DOI:10.1161/CIRCRESAHA.107.168682   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to fibroblast growth factor stimulus  IEP 7421597 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Vegfa  (vascular endothelial growth factor A)


Additional Information