title: Platelet-derived growth factor-BB mediates cell migration through induction of activating transcription factor 4 and tenascin-C.
abstract: The acute response to vascular cell injury, which underpins vasculo-occlusive pathologies such as atherogenesis and restenosis after percutaneous coronary intervention, involves a complex series of molecular events that alter patterns of gene expression and favor a synthetic phenotype. One transcription factor that has been implicated in this process is the evolutionarily conserved mammalian stress response pathway regulator activating transcription factor 4 (ATF-4). Here, we show for the first time that both mRNA and protein levels of ATF-4 are induced in smooth muscle cells (SMCs) by the potent migratory factor PDGF-BB through PDGFR-β. PDGF-BB also stimulates the expression of tenascin-C (TN-C), an extracellular matrix glycoprotein that regulates the activity of focal adhesion complexes, facilitating the SMC migration that underlies negative vascular remodeling in response to injury. Overexpression of ATF-4 increased transcript levels of the four TN-C isoforms in rat vascular SMCs, and ATF-4 knockdown inhibited PDGF-BB-inducible TN-C expression in vitro and injury-inducible TN-C protein expression in the balloon-injured rat artery wall. Furthermore, we show that ATF-4 is required for PDGF-BB-inducible SMC migration in response to injury. PDGF-BB-induced migration was also compromised in ATF-4 null mEFs, and this effect was rescued by the addition of TN-C. Our findings thus demonstrate the role of ATF-4 in both injury- and PDGF-BB-inducible TN-C expression and cell migration.
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, Australia.
authors.forename: Kristine P
authors.initials: KP
authors.lastname: Malabanan
authors.forename: Anjali V
authors.initials: AV
authors.lastname: Sheahan
authors.forename: Levon M
authors.initials: LM
authors.lastname: Khachigian
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D000818:Animals; D000077214:Becaplermin; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000503:physiopathology; D017536:Carotid Artery, Common / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000502:physiology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology; D019063:Tenascin / Q000096:biosynthesis* / Q000235:genetics; D014945:Wound Healing / Q000502:physiology
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019063:Tenascin; D051701:Activating Transcription Factor 4; D000077214:Becaplermin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta