Published online before print December 9, 2004, doi: 10.1161/01.ATV.0000152725.76020.3c
© 2005 American Heart Association, Inc.
Vascular Biology |
GATA-6 Regulates Genes Promoting Synthetic Functions in Vascular Smooth Muscle Cells
From the Molecular Cardiology Research Center, Department of Medicine, University of Pennsylvania Health System, Philadelphia.
Correspondence to John J. Lepore, MD, Molecular Cardiology Research Center, University of Pennsylvania, 951 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail john.lepore{at}uphs.upenn.edu
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Abstract |
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Objective— Previous studies suggested the zinc-finger transcription factor GATA-6 inhibits vascular smooth muscle cell (VSMC) proliferation and promotes the contractile VSMC phenotype. The objective of this study was to identify bona fide target genes regulated by GATA-6 in VSMCs.
Methods and Results— Microarray analyses were performed comparing mRNA from rat aortic smooth muscle cells (SMCs) infected with either adenovirus encoding a dominant-negative GATA-6/engrailed fusion protein or with control adenovirus. These studies identified 122 genes differentially expressed by at least 2-fold, including multiple genes involved in cell–cell signaling and cell–matrix interactions. Among these, endothelin-1 and the angiotensin type1a (AT1a) receptor are known to be induced in VSMCs in response to inflammatory stimuli and to be expressed in a GATA-dependent manner in cardiac myocytes in response to hemodynamic stress. Consistent with these findings, the endothelin-1 and AT1a receptor promoters were activated by forced expression of GATA-6 and repressed by forced expression of GATA-6/engrailed. Surprisingly, genes encoding SMC contractile proteins were not altered, and myocardin-induced SMC differentiation was not impaired in GATA-6–/– embryonic stem cells.
Conclusions— These data demonstrate that in VSMCs, GATA-6 regulates a set of genes associated with synthetic SMC functions and suggest that this transcriptional pathway may be independent from myocardin-induced SMC differentiation.
An unbiased microarray screen of genes regulated by GATA-6 in VSMCs identified multiple genes involved in cell-cell signaling and cell-matrix interactions. The endothelin-1 and the AT1a receptor genes were shown to be direct GATA-6 target genes. These data suggest that GATA-6 plays a role in promoting synthetic functions in VSMCs.
Key Words: gene regulation • smooth muscle differentiation • vascular biology • GATA-6
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Introduction |
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During postnatal development, vascular smooth muscle cells (VSMCs) retain the capacity to proliferate and modulate their phenotype from a "contractile" cell to a "synthetic" cell.1,2 This plasticity is required for wound healing and angiogenesis but is also important in the pathogenesis of vasculoproliferative syndromes, including atherosclerosis and restenosis. The expression of most smooth muscle cell (SMC)–restricted cytoskeletal and contractile genes, including smooth muscle myosin heavy chain (SM-MyHC), SM
-actin, calponin-h1, and SM22, is dependent on serum response factor (SRF) binding to CC(AT)6 GG (or CArG) boxes located within promoters and intragenic enhancers of these genes.1,2 Recently, the cardiac- and smooth-muscle–restricted SAP (SAF-A/B, Acinus, PIAS) domain protein myocardin was identified as a potent transcriptional coactivator that binds SRF and activates SRF-dependent SMC genes.3–5 In contrast, much less is understood about the transcriptional program that regulates genes encoding synthetic SMC markers in response to vessel wall injury. GATA-6 is the only member of the GATA family of zinc-finger transcription factors expressed in VSMCs.6–10 Because of the critical roles of GATA factors in restricting the developmental potential of other cell lineages, it has been postulated that GATA-6 may regulate SMC development or differentiation.6–10 However, GATA-6 is not expressed in all SMCs, such as the visceral SMCs populating the gastrointestinal tract and uterus.9 Moreover, GATA-6 is also expressed in visceral endoderm, cardiac myocytes, and epithelial cells of the bronchial tree and gastrointestinal tract.8–11 Targeted deletion of GATA-6 in mice revealed a block in the differentiation of visceral endoderm, but the resultant lethality at embryonic day 6.5 precluded assessment of the function of GATA-6 in VSMCs.11
Several studies suggested that GATA-6 plays a role in maintaining the contractile VSMC phenotype. GATA-6 activates (weakly) the SM-MyHC promoter,12,13 and GATA-6 and the LIM domain protein cysteine-rich protein 2 (CRP2) can together activate SRF-dependent SMC gene transcription.14 In cultured VSMCs, GATA-6 mRNA is rapidly (albeit transiently) downregulated by mitogen stimulation,10 and overexpression of GATA-6 in proliferating VSMCs produces cell cycle arrest.15 After rat carotid artery injury, GATA-6 expression and DNA-binding activity are reduced in neointimal VSMCs, and adenoviral overexpression of GATA-6 limits the neointimal proliferative response.16 However, the findings that: (1) GATA-6 is not expressed in all SMCs, (2) GATA-6 is expressed in proliferating VSMCs during embryonic development,9 (3) most SMC-restricted transcriptional regulatory elements lack functionally important GATA-binding sites,1,2 (4) forced expression of myocardin alone activates SRF-dependent SMC genes,3–5 and (5) GATA-6 regulates genes expressed in cardiac myocytes and SMCs,17 strongly suggest that the function of GATA-6 in VSMCs must be more complex than simply promoting a contractile SMC phenotype.
To identify genes activated or repressed by GATA-6 in VSMCs, we performed an unbiased microarray screen. Surprisingly, this screen identified multiple genes involved in cell–cell signaling and cell–matrix interactions. In particular, the genes encoding the angiotensin type1a (AT1a) receptor, endothelin-1, and vascular cell adhesion molecule-1 (VCAM-1), which are known to be regulated by GATA factors in other cell types and to be induced in SMCs by inflammatory stimuli,18–24 were repressed by expression of dominant-negative GATA-6. Consistent with these findings, reporter constructs containing the AT1a receptor and endothelin-1 promoters were activated by forced expression of GATA-6 and repressed by forced expression of dominant-negative GATA-6. In contrast, expression of genes encoding SMC-restricted cytoskeletal and contractile proteins was not altered by dominant-negative GATA-6, and the ability of myocardin to induce expression of these genes was similar in wild-type and GATA-6–/– ES cells. Together, these data are consistent with a model wherein GATA-6 activates a set of genes involved in cell–cell and cell–matrix interactions associated with synthetic SMC functions such as the response of VSMCs to arterial injury.
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Methods |
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Generation and Characterization of Replication-Defective Recombinant Adenoviruses
The adenovirus Ad-GATA-6/engrailed encodes a fusion protein consisting of the zinc-finger DNA-binding domain of GATA-6 and the repressor domain of the Drosophila engrailed protein, which we showed previously to function as a potent and specific dominant-negative inhibitor of GATA-dependent transcription in vitro and in vivo.25,26 Because GATA-6 is the only GATA factor expressed in VSMCs, expression of GATA-6/engrailed in these cells specifically inhibits the function of GATA-6. Ad-myocardin and Ad–enhanced green fluorescent protein (EGFP) encode full-length human myocardin and EGFP, respectively. For details, please see http://atvb.ahajournals.org.
Microarray Analysis of Genes Regulated by GATA-6 in VSMCs
Microarray analyses comparing mRNA harvested 48 hours after infection of primary rat aortic SMCs with either Ad-GATA-6/engrailed or with control Ad-EGFP were performed using Affymetrix rat 230A GeneChip oligonucleotide arrays. (See online supplement.)
Quantitative Real-Time RT-PCR
Quantitative real-time RT-PCR analysis of a subset of differentially expressed genes was performed 12, 24, and 48 hours after adenoviral infection as described previously3 using the PCR primers listed in supplemental Table I (available online at http://atvb.ahajournals.org).
In Vitro ES Cell Differentiation System
Undifferentiated wild-type and GATA-6–/– ES cells were infected with Ad-myocardin or Ad-EGFP. After 72 hours, RNA was harvested for real-time RT-PCR quantification of expression of SMC-restricted genes as described.3 (See online supplement.)
Plasmid Constructs
The –1023- to 197-bp rat AT1a receptor promoter27 and the –204- to 180-bp human endothelin-1 promoter19 were generated by PCR using Ex Taq polymerase (Takara) and subcloned into pGL3-Basic (Promega) to generate the reporter plasmids –1-kb AT1aR-luc and –0.2-kb ET1-luc. PCR primers are listed in supplemental Table I. pcDNA3–GATA-6 encoding full-length mouse GATA-6, pcDNA3–mutGATA-6 containing mutations changing amino acids 293 and 294, cysteine and alanine, to serine and arginine (eliminating DNA binding), and pCDNA3–Eng encoding the engrailed repressor were described previously.9,26
Cell Culture, Transient Cotransfections, and Reporter Assays
Transient transfection experiments were performed in NIH3T3 cells and A7r5 rat aortic SMCs as described previously.3,9 (See online supplement.)
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Results |
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Efficient Infection of SMCs and ES Cells With Recombinant Adenoviruses
Approximately 60% of cultured SMCs infected with Ad-GATA-6/engrailed or Ad-EGFP expressed the GATA-6/engrailed fusion protein or the control EGFP protein, respectively. The efficiency of infection of ES cells with Ad-EGFP was nearly 100% (Figure I, available online at http://atvb.ahajournals.org).
Identification of Genes Activated or Repressed by Dominant-Negative GATA-6/Engrailed
To identify genes regulated by GATA-6 in VSMCs, we compared mRNA harvested from primary rat aortic SMCs infected with either Ad-GATA-6/engrailed or Ad-EGFP using oligonucleotide arrays. This methodology permitted an unbiased assessment of GATA-6–regulated genes, including 4700 full-length rat cDNAs and 10 500 rat expressed sequence tags (ESTs). Using multiple samples and stringent statistical analysis, 122 unique genes were identified that were either activated or repressed 
2-fold by expression of GATA-6/engrailed. The differentially expressed genes included 69 known cDNAs (Figure II, available online at http://atvb.ahajournals.org) and 53 ESTs (Table II, available online at http://atvb.ahajournals.org).
Surprisingly, the genes encoding SM-MyHC, SM -actin, calponin-h1, smoothelin, SM 
-actin, h-caldesmon, and SM22, which were all represented in the oligonucleotide arrays, were not repressed by dominant-negative GATA-6/engrailed. In contrast, genes that were activated or repressed by 2-fold included cell-signaling molecules or their receptors, extracellular matrix components, components of cell–cell and cell-adhesion complexes, regulators of the cell cycle, other transcription factors, and metabolic enzymes (Figure II). Among these, the genes encoding the AT1a receptor, endothelin-1, and VCAM-1, which are known to be regulated by GATA factors in other cell types, were repressed by expression of GATA-6/engrailed, consistent with their being activated by GATA-6. Together, the microarray analyses suggest strongly that GATA-6 plays an unanticipated role in regulating genes that promote synthetic SMC functions.
Real-Time RT-PCR Analysis of Genes Regulated by GATA-6 in VSMCs
To validate observed changes in gene expression, we examined the mRNA of a subset of 12 genes known to play a role in VSMC cell–cell signaling and cell–matrix interaction using quantitative real-time RT-PCR. These studies confirmed that the natriuretic peptide receptor 1, VCAM-1, cysteine-rich protein 1, osteoprotegerin, endothelin-1, the AT1a receptor, matrilin, nidogen, SH3-binding protein 5, Arg/Abl-interacting protein ArgBP2, nexilin, and new EST tetraspan-2 (NET-2) were repressed by GATA-6/engrailed (Table), suggesting they are directly or indirectly activated by GATA-6. In contrast, expression of SRF-dependent, SMC-restricted genes, including SM-MyHC, SM -actin, calponin-h1, and SM22, was not significantly changed (Table).
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To examine the effect of GATA-6/engrailed on expression of SRF-dependent genes and putative GATA-6 target genes over time, we repeated the quantitative RT-PCR studies using mRNA harvested from rat aortic SMCs harvested 12, 24, and 48 hours after infection with Ad-GATA-6/engrailed or Ad-EGFP. These studies demonstrated that expression of SM-MyHC, SM -actin, SM22, and calponin-h1 was not significantly changed at any time point. In contrast, expression of GATA-6/engrailed resulted in a >2-fold decrease in expression of the AT1a receptor beginning at 12 hours and of VCAM-1 and endothelin-1 beginning at 24 hours after adenoviral infection, and these changes persisted 48 hours after adenoviral infection (Table III, available online at http://atvb.ahajournals.org). These studies demonstrated that the expression changes observed in the microarray studies are consistently observed at multiple time points after expression of GATA-6/engrailed.
GATA-6 Activates AT1a Receptor and Endothelin-1 Promoters in Nonmuscle Cells
Previous studies reported that consensus GATA-binding sites are important for regulation of AT1a receptor and endothelin-1 promoters in cardiac myocytes (by GATA-4) and in endothelial cells (by GATA-2).18,19,21 To determine whether GATA-6 also transactivates these promoters, transient cotransfection experiments in NIH3T3 fibroblasts were performed using luciferase reporter constructs under the transcriptional control of the –0.2-kb human endothelin-1 promoter or the –1.0-kb rat AT1a receptor promoter. Cotransfection with the pcDNA3–GATA-6 expression plasmid resulted in 4.7±0.1-fold and 12.9±0.4-fold activation of –0.2-kb ET1-luc and –1-kb AT1aR-luc, respectively (Figure 1, gray bars). In contrast, cotransfection with pcDNA3–mutGATA-6 did not increase luciferase activity, indicating that transcriptional activation of these promoters is dependent on zinc finger–mediated binding of GATA-6 to DNA (Figure 1, white bars). These data demonstrate that endothelin-1 and AT1a receptor promoters are directly activated by GATA-6 in non-SMCs and suggest strongly that endothelin-1 and AT1a receptor gene expression is regulated by GATA-6 at the transcriptional level.
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AT1a Receptor and Endothelin-1 Promoters Are Repressed by Dominant-Negative GATA-6 in SMCs
To determine whether GATA-6 regulates endothelin-1 and AT1a transcription in VSMCs, A7r5 SMCs were cotransfected with an expression plasmid encoding GATA-6/engrailed and luciferase reporter plasmids under transcriptional control of either the endothelin-1 or AT1a receptor promoter. Forced expression of increasing amounts of the GATA-6/engrailed fusion protein resulted in dose-dependent reductions of the baseline luciferase activity of the –0.2-kb endothelin-1 and the –1.0-kb AT1a receptor reporter plasmids (Figure 2 A and 2B, respectively, white bars). In contrast, forced expression of engrailed protein alone did not significantly affect the activity of either promoter (Figure 2A and 2B, gray bars) or that of multiple non–GATA-dependent reporter plasmids including Rous sarcoma virus–ß-galactosidase (ß-gal), murine sarcoma virus–ß-gal, and pRL-SV40-d238 (data not shown). Together, these findings demonstrate that the transcriptional activity of the endothelin-1 and AT1a receptor promoters in VSMCs is dependent on GATA-6, strongly suggesting that these genes are direct transcriptional targets of GATA-6 in VSMCs.
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GATA-6 Is Not Required for Myocardin-Induced Expression of Endogenous SMC Genes in Undifferentiated ES Cells
Forced expression of myocardin induces expression of multiple SRF-dependent, SMC-restricted genes, including SM-MyHC, SM -actin, calponin-h1, and SM22 in undifferentiated ES cells.3–5 We tested whether myocardin-induced SMC differentiation was altered in GATA-6–/– ES cells. Forced expression of myocardin in wild-type and GATA-6–/– ES cells resulted in robust induction of the endogenous SM-MyHC, SM -actin gene, calponin-h1, and SM22 genes (Figure 3). These studies demonstrated that GATA-6 is not required for the myocardin-induced expression of these genes encoding contractile SMC markers.
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Discussion |
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GATA-6, a member of an evolutionarily conserved family of zinc-finger transcription factors that play critical roles in regulating cellular differentiation, is expressed abundantly in VSMCs throughout embryonic and postnatal development.8–10 To identify genes regulated by GATA-6 in VSMCs, a microarray study was designed that minimized background noise from non-SMCs and from SMC heterogeneity related to passage number and conditions. The unbiased nature of this screen allowed us to identify genes unsuspected previously of being regulated by GATA-6. Surprisingly, we identified multiple genes encoding growth factors and their receptors, extracellular matrix components, and cell–cell and cell–matrix adhesion molecules. These results were confirmed by quantitative real-time RT-PCR analyses. Importantly, the genes we identified as being regulated by GATA-6 may not represent the entire transcriptional program regulated by GATA-6 in VSMCs. The advantage of our microarray study design was that it allowed a genomewide analysis of the transcriptional program regulated by GATA-6 in a tightly controlled experiment in which the only variable was the expression of dominant-negative GATA-6.
Many of the GATA-6 target genes identified in this screen are involved in the inflammatory response and have been implicated in the pathogenesis of vascular proliferative syndromes including atherosclerosis. The natriuretic peptide receptor 1 is involved in blood pressure regulation and may play a role in VSMC growth during atherogenesis.28 VCAM-1 is a cell-adhesion molecule that is induced in VSMCs by inflammatory cytokines and is implicated in the pathogenesis of atherosclerosis and neointimal proliferation.23 Cysteine-rich protein 61 is an extracellular matrix–associated protein that promotes VSMC adhesion and chemotaxis and is upregulated in medial VSMCs after arterial injury.29 Osteoprotegerin, a secreted osteoclast-activating factor, is also expressed in VSMCs, in which it is implicated in vascular calcification and atherogenesis.30 Endothelin-1 is a potent vasoconstrictor agent and VSMC growth factor that is induced in VSMCs by inflammatory stimuli.22 The AT1a receptor is the principal receptor for angiotensin II, a potent SMC mitogen and growth factor that is upregulated in VSMCs by vascular injury.31 Matrilin and nidogen are vascular extracellular matrix components,32,33 and SH3-domain binding protein 5, Arg/Abl-interacting protein ArgBP2, nexilin, and tetraspan NET-2 are components of multimeric cell–cell and cell–matrix-adhesion complexes.34–36 Together, these data suggest that GATA-6 lies upstream in a transcriptional program regulating, in part, VSMC responsiveness to growth factors and to arterial injury.
Several reports have suggested that the major function of GATA-6 in VSMCs is to promote SMC differentiation and cell cycle arrest.12–16,37 However, the data presented herein suggest that the function of GATA-6 may be more complex than simply promoting the contractile, quiescent phenotype. Endogenous contractile SMC-restricted genes, including SM-MyHC, SM22, calponin-h1, and SM -actin, were not repressed by expression of dominant-negative GATA-6. This finding was not entirely surprising because with the exception of SM-MyHC, these genes lack functionally important GATA-binding sites in their promoters and transcriptional enhancers. Moreover, these genes are expressed at high levels in gastrointestinal and uterine SMCs, which do not express GATA-6 (or other GATA factors).9 Finally, robust myocardin-induced expression of SMC contractile genes was observed in GATA-6–/– ES cells. In this regard, it is notable that expression of GATA-6 is not induced during myocardin-induced expression of SMC marker genes in wild-type ES cells (data not shown), further supporting the conclusion that GATA-6 is not required for expression of these genes. In addition, we have not observed compensatory induction of GATA-4 or GATA-5 expression during myocardin-induced SMC differentiation in GATA-6–/– ES cells (data not shown). Thus, although it remains possible that multiple, redundant transcriptional programs promote SMC differentiation, or that induction of other GATA factors or unrelated transcription factors can compensate for GATA-6 in GATA-6–/– ES cells, our data strongly support the conclusion that GATA-6 is not required for expression of SRF-dependent, SMC-restricted contractile proteins.
The microarray analyses also did not confirm that GATA-6 promotes SMC cell cycle arrest as reported previously.15,16 Although the genes encoding cyclin D1 and p55CDC were activated by GATA-6/engrailed, suggesting that GATA-6 represses these genes that promote cell cycle progression, the genes encoding cyclin-dependent kinase inhibitors 1C and 3 were also activated by GATA-6/engrailed, suggesting that GATA-6 represses these genes that inhibit cell cycle progression.38 Future studies including experiments involving loss of GATA-6 function in vivo will be required to elucidate the role of GATA-6 in regulating VSMC cell cycle progression.
Importantly, the microarray analyses identified 2 GATA-6–regulated genes, endothelin-1 and the AT1a receptor, that were shown previously to be activated directly by GATA-4 in cardiac myocytes, promoting cardiac hypertrophy in response to hypertrophic stimuli.18,21 Similarly, in VSMCs, endothelin-1 and angiotensin II (acting through the AT1a receptor) promote growth, hypertrophy, and modulation of SMC phenotype from contractile to synthetic.39–41 Moreover, in VSMCs, endothelin-1 and AT1a receptor gene expression is induced by inflammatory stimuli including cytokines, CRP, and vascular injury.22,24,31 Activation of these genes by GATA-6 in VSMCs is direct because the endothelin-1 and AT1a receptor promoters contain consensus GATA-binding sites, were transactivated by GATA-6 in non-SMCs, and were repressed by dominant-negative GATA-6 in VSMCs. These data suggest that a conserved function of GATA factors in cardiac myocytes and VSMCs is to transduce hemodynamic and humoral stimuli, which, in turn, activates transcriptional programs required for cellular adaptation to these stimuli. In cardiac myocytes, this leads to myocyte hypertrophy, whereas in VSMCs, this contributes to modulation of phenotype from contractile to synthetic.
Our finding that GATA-6/engrailed repressed expression of multiple genes associated with the VSMC synthetic phenotype but did not repress expression of genes encoding SRF-dependent, SMC-restricted contractile proteins is consistent with the observation that downregulation of SMC contractile proteins and expression of genes required for the proliferative, synthetic phenotype are not tightly functionally coupled.1,2 For example, SMC contractile proteins are highly expressed in VSMCs during embryonic development, even when these cells are rapidly proliferating and producing extracellular matrix. Similarly, SMCs in the fibrous caps of atherosclerotic lesions express relatively high levels of some SMC contractile proteins. Thus, our findings are consistent with a model wherein GATA-6 regulates multiple genes associated with the synthetic SMC functions but is not required for myocardin- and SRF-dependent expression of genes encoding contractile markers.
Together, the set of genes identified in this study as bona fide GATA-6 target genes in VSMCs suggests that GATA-6–mediated mechanisms may play a critical role in the transcriptional program regulating VSMC growth and adaptation and may underlie some aspects of vascular proliferative syndromes including atherosclerosis.
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Acknowledgments |
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This work was supported in part by an allocation from the Commonwealth of Pennsylvania and by grants from the Mary L. Smith Charitable Lead Trust to J.J.L. and from the National Institutes of Health to M.S.P. (PO1-HL075380 and RO1-HL56915) and E.E.M. (RO1-HL-64632). The authors thank Dr J. Tobias of the Penn Bioinformatics Core for assistance with microarray studies.
Received August 20, 2004; accepted November 29, 2004.
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