Published online before print July 10, 2008, doi: 10.1161/CIRCRESAHA.107.168682
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© 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
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
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Abstract |
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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
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Injury to the artery wall triggers a complex sequence of cellular events, including the accumulation of smooth muscle cells (SMCs) in the intima. SMC growth contributes to the formation of the lesion and loss of lumen diameter and vascular contractility, which underpin such pathologies as atherosclerosis and restenosis after balloon angioplasty. At the molecular level, these events are initiated and maintained by transcription factors. Activation of transcription factors can result in the altered expression of pathophysiologically relevant genes, making key transcription factors potential therapeutic targets. Numerous transcription factors are induced in the vascular SMC response to injury, including nuclear factor
B,1 E2F,2 c-Jun,3 and Egr-1.4 A more complete understanding of the transcription factors regulating the response to injury would lead to more effective strategies to control vascular occlusive disorders. Activation transcription factor (ATF)-4 is a bZIP (basic leucine zipper domain) transcription factor that belongs to the cAMP-responsive element binding (CREB) protein family. Able to form heterodimers with members of the AP-1 and C/EBP family of proteins, ATF-4 (also known as CREB2, TAXREB67, C/ATF) can act either as an activator or as a repressor.5 ATF-4 is a regulator of pathways through which mammalian cells respond to amino acid deficiency.6 It controls genes involved in amino acid import, glutathione biosynthesis, and resistance to oxidative stress.7 Consequently, transcriptional upregulation of ATF-4 has been demonstrated in a variety of contexts: by nitric oxide in human monocytes,8 by homocysteine in human vascular endothelial cells,9 by superoxide in ischemic neurons,10 and by heregulin, a combinatorial ligand for human epidermal growth factor receptor-3 and for human epidermal growth factor receptor-4, in breast cancer cells.11 However, the expression of ATF-4 in the artery wall and its possible involvement in the response to injury have not yet been characterized.
In efforts to identify new transcription factors involved in the process of neointima formation, here, we used microarray studies to screen for key genes differentially expressed by rat aortic SMCs treated with fibroblast growth factor (FGF)-2, a growth factor that is released by injured vascular cells in vitro and in vivo12,13 and that has long been implicated in the pathogenesis of atherosclerosis and restenosis.14 We demonstrate ATF-4 induction by FGF-2 in vascular SMCs in vitro and in the medial compartment of balloon-injured rat carotid arteries. Moreover, we show that ATF-4 plays a critical role in the transcriptional induction of vascular endothelial growth factor (VEGF)-A, which is itself activated by both FGF-215,16 and balloon injury.17 We propose that ATF-4 serves as a key conduit for the injury-inducible expression of VEGF-A by FGF-2 in the reparative response to injury.
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Materials and Methods |
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Details on cell culture, plasmid construction and transient transfection, luciferase assays, RT-PCR and quantitative (Q)RT-PCR, immunoprecipitation, Western blotting, EMSA, SMC proliferation, the carotid artery injury, chromatin immunoprecipatation (ChIP), and immunohistochemistry can be found in the online data supplement at http://circre.ahajournals.org.
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Results and Discussion |
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ATF-4 Is Inducibly Expressed by Vascular SMCs in Response to Injury, In Vivo and In Vitro
Immunohistochemical analysis of uninjured rat carotid arteries revealed that ATF-4 is poorly expressed in medial SMCs. However, ATF-4 expression was readily detectable in these SMCs within 4 hours of injury (Figure 1A). To determine whether ATF-4 is expressed at longer time points after balloon injury, we stained the arteries for ATF-4, 5 days (when the neointima was starting to become visible) and 14 days (when an extensive neointima had formed) after balloon injury. ATF-4 staining was apparent in both the media and intima at these later time points, although staining intensity was considerably less intense compared to 4 hours postinjury (Figure 1A). Immunochemical analysis at all time points was performed simultaneously to avoid inconsistencies in staining and any difficulties interpreting the data.
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In support of these data, we injured cultured rat aortic SMCs in vitro using a well-established scraping model.18,19 RT-PCR analysis revealed that ATF-4 transcript levels increased after injury in a time-dependent manner (Figure 1B). The inducible expression of ATF-4 in this model followed that of the immediate early gene, early growth response-1 (Egr-1), which increased within 30 minutes (Figure 1B).20 QRT-PCR analysis revealed that ATF-4 transcript levels increased 2.5-fold within 2 hours of in vitro injury (Figure 1C). This is the first demonstration of the induction of ATF-4 by injury in vascular SMCs.
FGF-2 Stimulates ATF-4 Expression in Vascular SMCs
We next examined whether ATF-4 can be induced by FGF-2, because we and others have previously shown that injury triggers the rapid release of endogenous FGF-2 from SMCs.13 RT-PCR analysis of FGF-2–treated SMCs revealed increased ATF-4 expression within 1 to 2 hours of exposure to FGF-2, which remained elevated at 4 hours (Figure 2A). Real-time PCR analysis likewise demonstrated increased ATF-4 mRNA levels, reaching 2.5-fold after 4 hours (Figure 2B). Immunoprecipitation of ATF-4 from lysates of FGF-2–treated SMCs followed by immunoblotting for ATF-4 revealed increased levels of ATF-4 protein within 2 hours of growth factor exposure (Figure 2C, left). Substituting ATF-4 antibodies (rabbit polyclonal IgG isotype) with species- and isotype-matched antibodies in the immunoprecipitation step to nuclear factor B p65 did not give rise to an ATF-4 signal (Figure 2C, left). The induction of ATF-4 by FGF-2, like injury, has not been described previously in any cell type. ATF-4 expression was unchanged up to 4 hours after bovine aortic endothelial cells were exposed to FGF-2 or in vitro injury (data not shown), suggesting cell-restricted regulation of ATF-4 expression.
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To provide confirmatory evidence linking ATF-4 with endoplasmic reticulum stress in SMCs, we performed Western blot analysis using extracts of SMCs various times after scraping injury or exposure to FGF-2. It is well established that endoplasmic reticulum stress activates PERK-dependent eIF2
phosphorylation and that this axis lies upstream of ATF-4 expression.7 Our data show that both injury and FGF-2 increase phospho-eIF2 levels within 1 hour (Figure 2C, right).
Pathways of ATF-4 Activation
To determine the signaling pathways through which FGF-2 activates ATF-4, established pharmacological inhibitors of 2 known kinase pathways were used 1 hour before 4 hours of treatment with FGF-2. QRT-PCR analysis revealed that the phosphatidylinositol 3-kinase (PI3K) inhibitor LY29400221 blocked FGF-2–dependent induction of ATF-4. In contrast, the extracellular signal-regulated kinase (ERK) inhibitor PD9805922,23 had no effect (Figure 3A, top). Western blot analysis for the phosphorylated form of Akt verified the activation of the PI3K pathway by FGF-2 and inhibition of this process by LY294002 (Figure 3A, bottom). Immunohistochemical staining confirmed that Akt phosphorylation is increased within 4 hours of injury (Figure 3B). Phospho-Akt levels remain elevated 5 and 14 days after injury (Figure 3B).
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ATF-4 Overexpression Increases VEGF-A Levels
VEGF-A exacerbates the mitogenic effect of FGF-2 in the injured vessel wall. Pretreatment with VEGF-A has been found to significantly increase intimal SMC replication in response to FGF-2 in rat carotid arteries, as compared to infusion with FGF-2 alone.24 To establish a regulatory role for ATF-4 as a mediator of FGF-2–inducible VEGF-A expression, the CMV-driven expression vector pcDNA3.1/ATF-4 (20 µg) was transfected into rat aortic SMCs, and the backbone (pcDNA3.1) was used as control. ATF-4 overexpression induced VEGF-A mRNA levels (Figure 4A). ATF-4 also increased the expression of numerous other genes that had been differentially expressed in the ATF-4+/+ versus ATF-4–/– mouse embryonic fibroblast (MEF) screen, including platelet-derived growth factor (PDGF) receptor-, cholesterol 25-hydroxylase, and angiotensin II receptor 2 (Figure 4A). On the other hand, PDGF-A levels remained unchanged (Figure 4A). We further observed a 4-fold increase in the expression of VEGF-164, the VEGF-A isoform predominantly expressed in SMCs, in ATF-4 transfectants as compared to the backbone alone (Figure 4B).
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FGF-2 Induces ATF-4 Binding to a Recognition Element Located in the VEGF-A Gene at +1767 bp and Luciferase Expression Dependent on This Site
QRT-PCR analysis of FGF-2–treated SMCs shows that FGF-2 induced transcription of VEGF-A 8 hours after exposure to FGF-2 (Figure 5), consistent with the induction observed with ATF-4 (Figure 4). Previous studies have demonstrated the existence of a single functional ATF-4 binding site in the VEGF-A gene.25 A 32P-labeled double-stranded oligonucleotide spanning this element was used in electrophoretic mobility-shift assay (EMSA), together with extracts of SMCs exposed to FGF-2 for 2 hours. Incubation with FGF-2 induced nucleoprotein complex formation, which was competed for by a 100-fold excess of unlabeled Oligo VEGF-A1752/1786, but not by mOligo VEGF-A1752/1786, in which the ATF-4 recognition element was mutated (5'-GATTACATC-3' to 5'-AATCATACA-3') (Figure 6A, top). FGF-2–inducible nucleoprotein complex formation was also abolished by the presence of a molar excess of ATF-4 Oligo, an oligonucleotide bearing a consensus ATF-4 binding site (Figure 6A, top).26 We also used a commercial preparation of recombinant human ATF-4 protein in EMSA. The protein formed a complex with 32P-Oligo VEGF-A1752/1786, whereas 32P-mOligo VEGF-A1752/1786 failed to form this complex (Figure 6A, middle). We next performed the EMSA with nuclear extracts of SMCs 2 hours after scraping injury, when ATF-4 expression is clearly increased (Figure 1B). Injury-inducible nucleoprotein complex formation was abrogated by a molar excess of unlabeled Oligo VEGF-A1752/1786 or ATF Oligo, and 32P-mOligo VEGF-A1752/1786 did not form an inducible complex (Figure 6A, bottom). Extending these findings, we performed ChIP analysis with extracts of cells untreated or treated with FGF-2 for 2 hours. Figure 6B demonstrates that endogenous ATF-4 binds to the authentic VEGF-A gene in cells exposed to FGF-2, whereas the amplicon is not bound by p65 or YY1.
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To determine whether FGF-inducible ATF-4 is able to transactivate from this site in the human VEGF-A gene, this nucleotide motif was cloned into pGL3prom, to create pGL3prom-VEGF-A1752/1786, pGL3prom-VEGF-Am1752/1786 (the oligonucleotide bearing the mutant sequence) and pGL3prom-VEGF-Arev1752/1786 (oligonucleotide in reverse orientation). These constructs were transfected into SMCs and then treated with FGF-2 for 24 hours. Luciferase assays revealed that FGF-2 stimulated expression from this element in pGL3prom-VEGF-A1752/1786 and pGL3prom-VEGF-Arev1752/1786 but not pGL3prom-VEGF-Am1752/1786 nor the backbone pGL3prom alone (Figure 6C). This complements the binding data and provides the first demonstration that ATF-4 mediates FGF-2–inducible reporter gene expression dependent on the VEGF-A ATF-4 element.
ATF-4 Deficiency Ameliorates FGF-2–Inducible VEGF-A Expression
To examine the effect of ATF-4 deficiency on FGF-2–inducible VEGF-A expression, we next used SV40-transformed embryonic fibroblasts derived from ATF-4+/+ and ATF-4–/– mice. QRT-PCR analysis demonstrates a 4-fold reduction in VEGF-A transcript levels in ATF-4–/– MEFs as compared to the ATF-4+/+ MEFs at all time points between 2 and 8 hours after exposure to FGF-2 (Figure 7A). In addition, small interfering (si)RNA targeting ATF-4 (0.4 µmol/L siRNA) blocked FGF-2 induction of ATF-4 expression after 4 hours in SMCs, whereas the scrambled siRNA counterpart failed to inhibit (Figure 7B). Moreover, the ATF-4 siRNA prevented FGF-inducible VEGF-A mRNA levels after 8 hours, compared to VEGF-A levels in untreated SMCs (Figure 7C).
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ATF-4 siRNA Blocks Injury-Inducible VEGF-A Expression and Neointima Formation in Balloon-Injured Carotid Arteries
Finally, to determine whether ATF-4 regulates the process of intimal hyperplasia in response to injury, we balloon-injured rat carotid arteries,18,27 then infused ATF-4 siRNA (50 µg bolus) intraluminally for 20 minutes, and then performed immunohistochemistry 4 hours and 14 days after injury. ATF-4 siRNA virtually abrogated ATF-4 expression at 4 hours (Figure 8A), when levels of ATF-4 in control injured arteries are at their highest of all time points examined (Figure 1A). By 14 days postinjury, although ATF-4 expression is comparatively weaker (Figure 1A), the siRNA still reduced ATF-4 expression (Figure 8A). In contrast, ATF-4 immunostaining was not influenced by the control siRNA (ATF-4 siRNAscr), with scrambled sequence (Figure 8A). Also, importantly, VEGF-A induced by injury was blocked by the ATF-4 siRNA (Figure 8B). Morphometric analysis 14 days after balloon injury demonstrates a reduction in intimal thickening (Figure 8C and 8D). These data link VEGF-A with ATF-4 in balloon-injured arteries and demonstrate the dependency of VEGF-A expression on ATF-4 in the vessel. ATF-4 is necessary for intimal thickening in rat carotid arteries after vascular injury. We did not observe any significant mitogenic effect of VEGF-A (unlike FGF-2) on SMC growth after 3 days (Figure 8E, top), consistent with previous reports.28 ATF-4 overexpression, on the other hand, stimulated SMC proliferation after 3 days, and this growth was unaffected by the presence of neutralizing VEGF-A antibodies (Figure 8E, bottom). These data demonstrate that the mitogenic effect of ATF-4 on SMCs is mediated by factors other than VEGF-A.
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This study provides the first demonstration of ATF-4 induction in vascular SMCs by arterial balloon injury in vivo and mechanical injury in vitro. It is also the first demonstration of the activation of ATF-4 mRNA, protein, and DNA-binding by FGF-2, an injury-induced growth factor, through the PI3K pathway. Because ATF-4 is associated with cellular stress and, in particular, endoplasmic reticulum stress,29 our findings are supported by previous reports that have linked endoplasmic reticulum stress with the development of atherogenesis30 and ischemic heart disease.31 The present findings also demonstrate that ATF-4 is both necessary and sufficient to induce VEGF-A transcription; the absence of ATF-4 perturbs FGF-2–inducible VEGF-A transcription, in both vascular SMCs and in MEFs. VEGF-A expression by medial SMCs is suppressed when ATF-4 is silenced using siRNA.
VEGF-A is a secreted glycoprotein and a potent angiogenic factor, regulating embryonic, physiological, and pathological blood vessel growth in vivo.32 Although originally identified as an endothelial cell mitogen and vascular permeability factor, it is now clear that VEGF-A plays significant roles in other cell types and contexts.33 With at least 5 known isoforms, its expression is regulated at multiple levels, including transcription, in which AP-1, Sp1, Egr-1, and HIF-1 play a role.34 Like other growth regulatory genes, such as FGF-2 and PDGF-A, transcription of VEGF-A is made more complex by the presence of a long (1-kb) and G+C-rich 5' untranslated region that carries secondary structure.35 It would not be surprising that elements outside the VEGF-A proximal promoter would play a role in regulating its transcription. Our results indicate that an element located +1767 bp in the VEGF-A gene is bound by ATF-4 in response to FGF-2 (Figure 6A, top, and 6B) and injury (Figure 6A, bottom) and confers responsiveness of a heterologous construct to FGF-2 (Figure 6C). Specificity of both binding and transactivation by ATF-4 is evidenced by ablation of this effect when the ATF-4 site was mutated. We have previously investigated growth factor regulation of another growth factor at the level of transcription. For example, Egr-1 mediates FGF-1–induced PDGF-A chain expression in endothelial cells.36 Egr-1 also controls increased PDGF-C transcription in SMCs exposed to FGF-2.37 PDGF-BB stimulates PDGF-A in SMCs via Ets-1 and Sp1.38
FGF-2 is an important activator of gene expression programs in the injured artery wall because of its existence in a preformed state in uninjured arteries and its rapid release on injury. Our own work has shown that FGF-2 is released within 5 minutes in stented human coronary arteries, whereas transforming growth factor-β and P-selectin levels are unchanged.12 Interestingly, ATF-4 expression is induced by a number of factors other than FGF-2 that have been implicated in atherogenesis and intimal hyperplasia, such as nitric oxide,8 osteopontin,39 and homocysteine.40 It is, therefore, unlikely that FGF-2 is the only mediator of inducible ATF-4 expression. Future studies should determine whether ATF-4 functionally regulates the effects of injury-induced factors other than FGF-2 in the artery wall. Our studies also open up opportunities of exploring the role of ATF-4 in the regulation of pathophysiologically relevant genes besides VEGF-A. These include PDGF receptor-,41 cholesterol 25-hydroxylase,42 and angiotensin II receptor 2.43 Consistent with this, there are numerous putative ATF-4 binding motifs in the promoters of these genes. Interestingly, ATF-4 increases PDGF receptor- expression without affecting levels of PDGF-A. These findings broaden the scope of ATF-4 target genes beyond VEGF-A and implicate ATF-4 as a key regulator in SMC pathobiology. It will also be interesting to explore the functional interrelationship between ATF-4 and other transcription factors (such as Egr-1,4,44,45 c-Jun,3 and Ets-146) that are also induced by injury. The ATF-4 promoter contains several putative binding sites for Egr-1, c-Jun/AP-1, and Ets-1, suggesting that the expression of ATF-4 may be influenced by these SMC injury-inducible transcription factors. ATF-4 may also regulate these other transcription factors through protein:protein interactions. Although the capacity of ATF-4 to interact with Egr-1 and Ets-1 has not yet been reported, its ability to bind and functionally cooperate with other transcription factors is well established.47,48
The role of VEGF-A in vascular injury is poorly understood. VEGF-A mRNA and protein levels are increased in endothelium-denuded porcine arteries17 and in balloon-injured rabbit arteries.49 On one hand, some reports indicate that VEGF-A is an endothelial cell mitogen with poor, if any, positive influence on SMC proliferation.28 VEGF-A is thought to attenuate SMC hyperplasia by stimulating reendothelialization.50,51 On the other hand, several lines of evidence indicate that VEGF-A stimulates neointima formation. For example, local gene transfer of VEGF-A significantly increases intimal hyperplasia after balloon injury49 or application of silastic collars.52 Intraluminal infusion of VEGF-A to denuded rat carotid arteries doubled the mitogenic response to infused FGF-2 by increasing intimal SMC replication.24 Moreover, systemic delivery of soluble Flt1 (which blocks VEGF-A–VEGFR1/Flt1 binding) attenuated neointima formation after balloon injury without affecting luminal reendothelialization.53 The ability of VEGF-A to influence the behavior of nonendothelial cell types may be mediated by Flt-1, which is highly expressed in injured vessels.24 The VEGF-A-Flt-1 axis promotes the recruitment of SMCs and inflammatory cells,54 increasing matrix metalloproteinase production, which promote SMC migration.55 The present study does not intend to reconcile these apparently different paradigms. Instead, it integrates, for the first time, FGF-2 (which is well known to be released locally on acute vascular injury56) with VEGF-A expression in SMCs16 through PI3K-dependent ATF-4 induction and VEGF-A transactivation. Our findings show that silencing ATF-4 inhibits injury-inducible VEGF-A expression and intimal hyperplasia in rat carotid arteries. This defines a new role for ATF-4 as a phenotypic regulator in the vascular response to injury.
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Acknowledgments |
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We thank David Ron for kindly providing ATF-4+/+ and ATF-4–/– MEFs, Gavin McKenzie for technical help, Ryan Peden for invaluable contributions, and Fernando Santiago for critical comments.
Sources of Funding
This work was supported by grants from the National Health and Medical Research Council (Australia).
Disclosures
None.
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Footnotes |
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Original received November 26, 2007; revision received June 24, 2008; accepted June 26, 2008.
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References |
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