This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 103/4/378    most recent CIRCRESAHA.107.168682v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Malabanan, K. P. Articles by Khachigian, L. M. Search for Related Content PubMed PubMed Citation Articles by Malabanan, K. P. Articles by Khachigian, L. M. Related Collections Restenosis Gene regulation Related Article

(Circulation Research. 2008;103:378.)
© 2008 American Heart Association, Inc.

Molecular Medicine

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

Kristine P. Malabanan, Peter Kanellakis, Alexander Bobik, Levon M. Khachigian

From the Centre for Vascular Research (K.P.M., L.M.K.), School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney; and Baker Heart Research Institute (P.K., A.B.), Melbourne, Australia.

Correspondence to Levon M. Khachigian, PhD, DSc, Centre for Vascular Research, University of New South Wales, Sydney, 2052 Australia. E-mail L.Khachigian{at}unsw.edu.au

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.

Key Words: ATF-4 • FGF-2 • VEGF-A • intimal thickening

Related Article:

ATF-4 and Vascular Injury: Integration of Growth Factor Signaling and the Cellular Stress Response

Michael T. Chin
Circ. Res. 2008 103: 331-333. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				S. F. Abcouwer and C. N. Roybal Regulation of Vascular Endothelial Growth Factor A by Activating Transcription Factor 4 Circ. Res., October 24, 2008; 103(9): e118 - e118. [Full Text] [PDF]

				L. M. Khachigian, A. Bobik, P. Kanellakis, and K. Malabanan Response to Abcouwer and Roybal Circ. Res., October 24, 2008; 103(9): e119 - e119. [Full Text] [PDF]

				M. T. Chin ATF-4 and Vascular Injury: Integration of Growth Factor Signaling and the Cellular Stress Response Circ. Res., August 15, 2008; 103(4): 331 - 333. [Full Text] [PDF]