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Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia
The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal development and maturation of the vasculature, as well as how these mechanisms/processes are altered in vascular injury or disease. A major challenge in understanding differentiation of the vascular SMC is that this cell can exhibit a wide range of different phenotypes at different stages of development, and even in adult organisms the cell is not terminally differentiated. Indeed, the SMC is capable of major changes in its phenotype in response to changes in local environmental cues including growth factors/inhibitors, mechanical influences, cell-cell and cell-matrix interactions, and various inflammatory mediators. There has been much progress in recent years to identify mechanisms that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function. One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development. However, it is critical to recognize that overall control of SMC differentiation/maturation, and regulation of its responses to changing environmental cues, is extremely complex and involves the cooperative interaction of many factors and signaling pathways that are just beginning to be understood. There is also relatively recent evidence that circulating stem cell populations can give rise to smooth muscle-like cells in association with vascular injury and atherosclerotic lesion development, although the exact role and properties of these cells remain to be clearly elucidated. The goal of this review is to summarize the current state of our knowledge in this area and to attempt to identify some of the key unresolved challenges and questions that require further study.
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Y. Diao, S. Guthrie, S.-L. Xia, X. Ouyang, L. Zhang, J. Xue, P. Lee, M. Grant, E. Scott, and M. S. Segal Long-Term Engraftment of Bone Marrow-Derived Cells in the Intimal Hyperplasia Lesion of Autologous Vein Grafts Am. J. Pathol., March 1, 2008; 172(3): 839 - 848. [Abstract] [Full Text] [PDF]
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 T. E. Callis, Z. Deng, J.-F. Chen, and D.-Z. Wang Muscling Through the microRNA World Experimental Biology and Medicine, February 1, 2008; 233(2): 131 - 138. [Abstract] [Full Text] [PDF]
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T. Tanaka, H. Sato, H. Doi, C. A. Yoshida, T. Shimizu, H. Matsui, M. Yamazaki, H. Akiyama, K. Kawai-Kowase, T. Iso, et al. Runx2 Represses Myocardin-Mediated Differentiation and Facilitates Osteogenic Conversion of Vascular Smooth Muscle Cells Mol. Cell. Biol., February 1, 2008; 28(3): 1147 - 1160. [Abstract] [Full Text] [PDF]
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 K. Tanaka, M. Sata, T. Natori, J.-r. Kim-Kaneyama, K. Nose, M. Shibanuma, Y. Hirata, and R. Nagai Circulating progenitor cells contribute to neointimal formation in nonirradiated chimeric mice FASEB J, February 1, 2008; 22(2): 428 - 436. [Abstract] [Full Text] [PDF]
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S. Kennard, H. Liu, and B. Lilly Transforming Growth Factor- (TGF- 1) Down-regulates Notch3 in Fibroblasts to Promote Smooth Muscle Gene Expression J. Biol. Chem., January 18, 2008; 283(3): 1324 - 1333. [Abstract] [Full Text] [PDF]
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Y.-J. Han and P. de Lanerolle Naturally Extended CT {middle dot} AG Repeats Increase H-DNA Structures and Promoter Activity in the Smooth Muscle Myosin Light Chain Kinase Gene Mol. Cell. Biol., January 15, 2008; 28(2): 863 - 872. [Abstract] [Full Text] [PDF]
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A. J. Halayko, T. Tran, and R. Gosens Phenotype and Functional Plasticity of Airway Smooth Muscle: Role of Caveolae and Caveolins Proceedings of the ATS, January 1, 2008; 5(1): 80 - 88. [Abstract] [Full Text] [PDF]
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T. Yoshida MCAT Elements and the TEF-1 Family of Transcription Factors in Muscle Development and Disease Arterioscler. Thromb. Vasc. Biol., January 1, 2008; 28(1): 8 - 17. [Abstract] [Full Text] [PDF]
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M. Moustafa-Bayoumi, M. A. Alhaj, O. El-Sayed, S. Wisel, M. A. Chotani, Z. A. Abouelnaga, M. D. H. Hassona, K. Rigatto, M. Morris, G. Nuovo, et al. Vascular Hypertrophy and Hypertension Caused by Transgenic Overexpression of Profilin 1 J. Biol. Chem., December 28, 2007; 282(52): 37632 - 37639. [Abstract] [Full Text] [PDF]
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G. Lagna, M. M. Ku, P. H. Nguyen, N. A. Neuman, B. N. Davis, and A. Hata Control of Phenotypic Plasticity of Smooth Muscle Cells by Bone Morphogenetic Protein Signaling through the Myocardin-related Transcription Factors J. Biol. Chem., December 21, 2007; 282(51): 37244 - 37255. [Abstract] [Full Text] [PDF]
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K. A. Martin, B. L. Merenick, M. Ding, K. M. Fetalvero, E. M. Rzucidlo, C. D. Kozul, D. J. Brown, H. Y. Chiu, M. Shyu, B. L. Drapeau, et al. Rapamycin Promotes Vascular Smooth Muscle Cell Differentiation through Insulin Receptor Substrate-1/Phosphatidylinositol 3-Kinase/Akt2 Feedback Signaling J. Biol. Chem., December 7, 2007; 282(49): 36112 - 36120. [Abstract] [Full Text] [PDF]
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K. Lockman, J. M. Taylor, and C. P. Mack The Histone Demethylase, Jmjd1a, Interacts With the Myocardin Factors to Regulate SMC Differentiation Marker Gene Expression Circ. Res., December 7, 2007; 101(12): e115 - e123. [Abstract] [Full Text] [PDF]
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N. E. Hastings, M. B. Simmers, O. G. McDonald, B. R. Wamhoff, and B. R. Blackman Atherosclerosis-prone hemodynamics differentially regulates endothelial and smooth muscle cell phenotypes and promotes pro-inflammatory priming Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1824 - C1833. [Abstract] [Full Text] [PDF]
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T. Zhang, S. Zhuang, D. E. Casteel, D. J. Looney, G. R. Boss, and R. B. Pilz A Cysteine-rich LIM-only Protein Mediates Regulation of Smooth Muscle-specific Gene Expression by cGMP-dependent Protein Kinase J. Biol. Chem., November 16, 2007; 282(46): 33367 - 33380. [Abstract] [Full Text] [PDF]
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M. Zamora, J. Manner, and P. Ruiz-Lozano Epicardium-derived progenitor cells require {beta}-catenin for coronary artery formation PNAS, November 13, 2007; 104(46): 18109 - 18114. [Abstract] [Full Text] [PDF]
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K. S. Beyer, R. L. Beauchamp, M.-F. Lee, J. F. Gusella, A. M. Naar, and V. Ramesh Mediator Subunit MED28 (Magicin) Is a Repressor of Smooth Muscle Cell Differentiation J. Biol. Chem., November 2, 2007; 282(44): 32152 - 32157. [Abstract] [Full Text] [PDF]
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 L. Li, C. M. Terry, D. K. Blumenthal, T. Kuji, T. Masaki, B. C. H. Kwan, I. Zhuplatov, J. K. Leypoldt, and A. K. Cheung Cellular and morphological changes during neointimal hyperplasia development in a porcine arteriovenous graft model Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3139 - 3146. [Abstract] [Full Text] [PDF]
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 E. A. Ashley, J. M. Spin, R. Tabibiazar, and T. Quertermous Frontiers in Nephrology: Genomic Approaches to Understanding the Molecular Basis of Atherosclerosis J. Am. Soc. Nephrol., November 1, 2007; 18(11): 2853 - 2862. [Abstract] [Full Text] [PDF]
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B. P. Herring and J. Zhou mCAT Got YouR TEF? Circ. Res., October 26, 2007; 101(9): 856 - 858. [Full Text] [PDF]
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Q. Gan, T. Yoshida, J. Li, and G. K. Owens Smooth Muscle Cells and Myofibroblasts Use Distinct Transcriptional Mechanisms for Smooth Muscle {alpha}-Actin Expression Circ. Res., October 26, 2007; 101(9): 883 - 892. [Abstract] [Full Text] [PDF]
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X. Long, E. E. Creemers, D.-Z. Wang, E. N. Olson, and J. M. Miano Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation PNAS, October 16, 2007; 104(42): 16570 - 16575. [Abstract] [Full Text] [PDF]
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N. A. Pidkovka, O. A. Cherepanova, T. Yoshida, M. R. Alexander, R. A. Deaton, J. A. Thomas, N. Leitinger, and G. K. Owens Oxidized Phospholipids Induce Phenotypic Switching of Vascular Smooth Muscle Cells In Vivo and In Vitro Circ. Res., October 12, 2007; 101(8): 792 - 801. [Abstract] [Full Text] [PDF]
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E. Wilson {alpha}7{beta}1 Integrin: Putting the Brakes on Smooth Muscle Cell Proliferation Circ. Res., September 28, 2007; 101(7): 651 - 653. [Full Text] [PDF]
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J. V. Welser, N. Lange, C. A. Singer, M. Elorza, P. Scowen, K. D. Keef, W. T. Gerthoffer, and D. J. Burkin Loss of the {alpha}7 Integrin Promotes Extracellular Signal-Regulated Kinase Activation and Altered Vascular Remodeling Circ. Res., September 28, 2007; 101(7): 672 - 681. [Abstract] [Full Text] [PDF]
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 E. Antonioli, A. B. Cardoso, and H. F. Carvalho Effects of Long-Term Castration on the Smooth Muscle Cell Phenotype of the Rat Ventral Prostate J Androl, September 1, 2007; 28(5): 777 - 783. [Abstract] [Full Text] [PDF]
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A. Kanematsu, A. Ramachandran, and R. M. Adam GATA-6 mediates human bladder smooth muscle differentiation: involvement of a novel enhancer element in regulating {alpha}-smooth muscle actin gene expression Am J Physiol Cell Physiol, September 1, 2007; 293(3): C1093 - C1102. [Abstract] [Full Text] [PDF]
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