Abstract
In response to vascular injury, differentiated vascular smooth muscle cells (vSMCs) undergo a unique process known as "phenotype modulation," transitioning from a quiescent, "contractile" phenotype to a proliferative, "synthetic" state. We have demonstrated previously that the signaling pathway of bone morphogenetic proteins, members of the transforming growth factor beta family, play a role in the induction and maintenance of a contractile phenotype in human primary pulmonary artery smooth muscle cells. In this study, we show that a four-and-a-half LIM domain protein 2 (FHL2) inhibits transcriptional activation of vSMC-specific genes mediated by the bone morphogenetic protein signaling pathway through the CArG box-binding proteins, such as serum response factor and members of the myocardin (Myocd) family. Interestingly, FHL2 does not affect recruitment of serum response factor or Myocd, however, it inhibits recruitment of a component of the SWI/SNF chromatin remodeling complex, Brg1, and RNA polymerase II, which are essential for the transcriptional activation. This is a novel mechanism of regulation of SMC-specific contractile genes by FHL2. Finally, aortic rings from homozygous FHL2-null mice display abnormalities in both endothelial-dependent and -independent relaxation, suggesting that FHL2 is essential for the regulation of vasomotor tone.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenoviridae / genetics
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Animals
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Aorta, Thoracic / cytology
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Aorta, Thoracic / metabolism*
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Blotting, Western
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Bone Morphogenetic Protein Receptors, Type II / genetics
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Bone Morphogenetic Protein Receptors, Type II / metabolism
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COS Cells
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Cells, Cultured
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Chlorocebus aethiops
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Chromatin Assembly and Disassembly
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Chromatin Immunoprecipitation
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DNA Helicases / genetics
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DNA Helicases / metabolism
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Fluorescent Antibody Technique
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Homeodomain Proteins / physiology*
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Humans
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LIM-Homeodomain Proteins
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Mice
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Mice, Knockout
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Muscle Proteins / genetics
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Muscle Proteins / metabolism*
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Muscle Proteins / physiology*
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phenotype
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Promoter Regions, Genetic
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Pulmonary Artery / cytology
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Pulmonary Artery / metabolism*
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RNA Polymerase II / genetics
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RNA Polymerase II / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Serum Response Factor / genetics
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Serum Response Factor / metabolism
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Signal Transduction
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription Factors / physiology*
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Transcriptional Activation
Substances
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FHL2 protein, human
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Fhl2 protein, mouse
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Homeodomain Proteins
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LIM-Homeodomain Proteins
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Muscle Proteins
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Nuclear Proteins
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RNA, Messenger
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Serum Response Factor
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Trans-Activators
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Transcription Factors
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myocardin
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Bmpr2 protein, mouse
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Bone Morphogenetic Protein Receptors, Type II
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RNA Polymerase II
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SMARCA4 protein, human
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DNA Helicases