doi: 10.1161/01.ATV.0000257573.32695.e1
© 2007 American Heart Association, Inc.
Editorials |
RhoA-Dependent Vascular Smooth Muscle Cell–Specific Transcription
Adding Diaphanous Formins to the Puzzle
From the Sahlgrenska Center for Cardiovascular and Metabolic Research, The Wallenberg Laboratory and Institute of Biomedicine, Department of Medical Chemistry and Cell Biology, Göteborg University, Sweden.
Correspondence to Dr Levent M. Akyürek, The Wallenberg Laboratory, Göteborg University, Bruna Stråket 16, SE-413 45 Göteborg, Sweden. E-mail levent.akyurek{at}wlab.gu.se
Phenotypic modulation of vascular smooth muscle cells (SMCs) plays an integral role in both vascular development and vasculoproliferative disorders. SMC-specific marker genes include caldesmon, smooth muscle myosin heavy chain, 
-smooth muscle actin, calponin, SM22, and - and ß-tropomyosins. Studies aimed at understanding the role of coactivators and corepressors of phenotypic modulation of SMC have been stimulated by the cloning and characterization of these SMC-specific genes and the discovery that the widely expressed serum response factor (SRF) is central to the expression of SMC-specific genes. SRF directly regulates the coordinated expression of several contractile and cytoskeletal genes through one or more CArG-box elements in the regulatory sequences of SMC-specific genes. This CArG-dependent program of SMC differentiation is modulated during both vascular development and arterial remodeling.1 Myocardin and myocardin-related transcription factors (MRTFs) bind to SRF, potently stimulate SRF-dependent transcription, and are necessary and sufficient for SMC differentiation.2 The RhoA pathway appears to activate myocardins by altering their binding to G-actins and causing translocation of myocardins from the cytoplasm to the nucleus.3 The regulation of the myocardins is key to understanding how SRF target genes are activated during SMC differentiation or growth factor-induced proliferation.
See page 478
The role of RhoA effectors in SMC-specific transcription and actin polymerization has not been extensively explored. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Staus et al studied two RhoA effectors, diaphanous formins 1 and 2 (Dia1 and Dia2), which activate SMC-specific transcription regulated by the myocardin family of SRF cofactors.4 These effectors belong to the subfamily of diaphanous-related formins.5 Formins are modular proteins that contain a series of domains and functional motifs and are potent regulators of actin dynamics.5 Most eukaryotes have multiple formin isoforms, suggesting diverse cellular roles. Although the precise mechanisms by which these formins stimulate actin polymerization are not well understood, Dia1/2 appear to promote polymerization from actin barbed ends in cooperation with an actin-binding protein, profilin.6,7 Staus et al demonstrated that Dia1/2 are expressed in many SMC-rich tissues. They proved that Dia1/2 signaling activated by RhoA induces SMC-specific promoter activity, requires the presence of SRF, and increases nuclear translocation of the myocardin-related transcription factors (Figure). To further support this model, the authors expressed a dominant-negative Dia1 variant that inhibits both Dia1 and Dia2 and demonstrated a decreased SMC-specific transcription in primary SMCs.
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These intriguing observations raise several questions that remain to be further studied. Molecular mechanisms that dissect the specific interaction not only between Dia1/2 and RhoA but also with RhoB and RhoC need to be identified. In fact, Dia1 is also recruited to endosomes by activated RhoB.8 A comparison of Dia1/2 activity with other RhoA effectors including ROK9 and PKN10 is also necessary to identify the dominating or overlapping signaling pathways that regulate SMC-specific transcription. These different RhoA effectors may positively or negatively operate with each other in a cell-specific manner.11 In addition to SMC-containing tissues, Staus et al demonstrated Dia1/2 expression in skeletal muscle,4 raising the possibility that these effectors may also be involved in differentiation of other muscle tissues. The development of a Dia1/2-deficient mouse line will be very useful to determine the biological importance of Dia1 or Dia2 for vascular development. The role of Dia1/2 in SMC-specific gene expression may be important not only for the vascular development, but also for the progression of atherosclerotic plaques. In this context, extracellular cues regulating Dia1/2 should be mapped.
The model that has further evolved here is that regulation of SMC differentiation is extremely complex. Given the fact that the contribution of circulating progenitor SMCs to vasculoproliferative human disorders is still controversial, it is important to investigate the phenotypic modulation of preexisting SMCs in response to microenvironmental cues and the genetic program that controls the coordinate SMC-specific expression. Future studies should focus on identifying and characterizing new pieces in the signaling pathways of SMC-specific transcription and their significance to both vascular development and vasculoproliferative disorders.
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Acknowledgments |
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We thank Rosie Perkins for editorial assistance.
Sources of Funding
This work was supported by a grant from the Swedish Heart Lung Foundation (to L.M.A.).
Disclosures
None.
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References |
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 Top References |
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3. Mack CP, Somlyo AV, Hautmann M, Somlyo AP, Owens GK. Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization. J Biol Chem. 2001; 276: 341–347.
4. Staus DP, Blaker AL, Taylor JM, Mack CP. Diaphanous 1 and 2 regulate smooth muscle cell differentiation by activating the myocardin-related transcription factors. Arterioscler Thromb Vasc Biol. 2007; 27: 478–486.
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8. Fernandez-Borja M, Janssen L, Verwoerd D, Hordijk P, Neefjes J. RhoB regulates endosome transport by promoting actin assembly on endosomal membranes through Dia1. J Cell Sci. 2005; 118: 2661–2670.
9. Chapados R, Abe K, Ihida-Stansbury K, McKean D, Gates AT, Kern M, Merklinger S, Elliott J, Plant A, Shimokawa H, Jones PL. ROCK controls matrix synthesis in vascular smooth muscle cells: coupling vasoconstriction to vascular remodeling. Circ Res. 2006; 99: 837–844.
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Related Article:
Arterioscler. Thromb. Vasc. Biol. 2007 27: 478-486.
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