The four-and-a-half LIM domain protein 2 regulates vascular smooth muscle phenotype and vascular tone.
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.
Mesh Terms:
Adenoviridae, Animals, Aorta, Thoracic, Blotting, Western, Bone Morphogenetic Protein Receptors, Type II, COS Cells, Cells, Cultured, Cercopithecus aethiops, Chromatin Assembly and Disassembly, Chromatin Immunoprecipitation, DNA Helicases, Fluorescent Antibody Technique, Homeodomain Proteins, Humans, Mice, Mice, Knockout, Muscle Proteins, Muscle, Smooth, Vascular, Nuclear Proteins, Phenotype, Promoter Regions, Genetic, Pulmonary Artery, RNA Polymerase II, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Serum Response Factor, Signal Transduction, Trans-Activators, Transcription Factors, Transcriptional Activation
Adenoviridae, Animals, Aorta, Thoracic, Blotting, Western, Bone Morphogenetic Protein Receptors, Type II, COS Cells, Cells, Cultured, Cercopithecus aethiops, Chromatin Assembly and Disassembly, Chromatin Immunoprecipitation, DNA Helicases, Fluorescent Antibody Technique, Homeodomain Proteins, Humans, Mice, Mice, Knockout, Muscle Proteins, Muscle, Smooth, Vascular, Nuclear Proteins, Phenotype, Promoter Regions, Genetic, Pulmonary Artery, RNA Polymerase II, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Serum Response Factor, Signal Transduction, Trans-Activators, Transcription Factors, Transcriptional Activation
J. Biol. Chem.
Date: May. 08, 2009
PubMed ID: 19265191
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