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

• Published in: Circulation research 2008-08, Vol.103 (4), p.378-387
• Main Authors: Malabanan, Kristine P, Kanellakis, Peter, Bobik, Alexander, Khachigian, Levon M
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Animals; Aorta - injuries; Aorta - metabolism; Biological and medical sciences; Carotid Artery Injuries - metabolism; Catheterization - adverse effects; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Endothelium, Vascular - cytology; Endothelium, Vascular - injuries; Endothelium, Vascular - metabolism; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Mice; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - injuries; Muscle, Smooth, Vascular - metabolism; Rats; Rats, Sprague-Dawley; RNA, Small Interfering - pharmacology; Signal Transduction - physiology; Tunica Intima - cytology; Tunica Intima - injuries; Tunica Intima - metabolism; Vascular Diseases - etiology; Vascular Diseases - metabolism; Vascular Endothelial Growth Factor A - metabolism; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.107.168682

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.