CONTROL OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE BY CGMP

Summary

Principal Investigator: Thomas Lincoln
Abstract: Smooth muscle cell gene expression controls the development and fate of vascular and non-vascular smooth muscle cells. In adult vascular smooth muscle cells (VSMC), the pattern of gene expression determines whether the cells exist in a contractile phenotype that is responsible for the control of vascular tone, or in a synthetic phenotype that is responsible for the repair of vessels in response to injury. The mechanism of VSMC-specific gene expression is a subject of interest since an understanding of the molecular control of this process may lead to a better understanding of the genesis of vascular disorders. One VSMC-specific transcriptional mechanism that has been defined is the serum response factor (SRF)-myocardin dependent regulation of VSMC-specific gene promoters. SRF-myocardin dependent gene regulation is modulated by many factors including the Ternary Factor Complex protein, Elk-1. Elk-1 is regulated by cellular signaling pathways such as growth factor-dependent phosphorylation and the small ubiquitin-like modifier protein (SUMO). Post-translational modification of Elk-1 by phosphorylation and sumoylation have been shown to alter SRF nuclear import and SRF-myocardin dependent mRNA expression. Likewise, the RhoA-Rho kinase signaling is also important for VSMC-specific gene expression because the RhoA pathway is involved in nuclear import of SRF. The nitric oxide (NO)-cGMP pathway stimulates VSMC-specific gene expression. Our laboratory has shown that the downstream mediator of NO-cGMP signaling, cGMP-dependent protein kinase (PKG), stimulates VSMC-specific gene expression but the mechanisms are undefined. We have obtained preliminary evidence that indicates that PKG stimulates sumoylation of Elk-1 in VSMC, and several laboratories have suggested that NO-cGMP signaling may be involved in the regulation of the RhoA-Rho kinase pathway. Both effects of PKG, Elk-1 SUMOylation and RhoA signaling, may shed light on the mechanism by which NO signaling increases VSMC-specific gene expression. This proposal is a basic science investigation to define the possible mechanisms by which PKG regulates VSMC-specific gene expression. The hypothesis is that PKG stimulates Elk-1 sumoylation, an effect which de-represses the action of Elk-1 on SRF/myocardin-dependent gene expression, and enhances RhoA signaling in cultured VSMC. These effects, in turn, stimulate SRF nuclear import and SRF-myocardin stimulated gene expression leading the cells to assume a contractile phenotype. The specific aims are to (1) determine the mechanism by which PKG increases SRF-dependent transcription via regulation of Elk-1 in rat aortic VSMC, and (2) to determine the mechanism by which PKG interacts with RhoA signaling to stimulate SRF-dependent gene expression.
Funding Period: 1995-07-01 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc Glc-6-PD and PKG contribute to hypoxia-induced decrease in smooth muscle cell contractile phenotype proteins in pulmonary artery
    Sukrutha Chettimada
    Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
    Am J Physiol Lung Cell Mol Physiol 303:L64-74. 2012
  2. pmc Glucose downregulation of PKG-I protein mediates increased thrombospondin1-dependent TGF-{beta} activity in vascular smooth muscle cells
    Shuxia Wang
    Univ of Kentucky, Lexington, 40536, USA
    Am J Physiol Cell Physiol 298:C1188-97. 2010
  3. pmc cGMP-dependent protein kinase and the regulation of vascular smooth muscle cell gene expression: possible involvement of Elk-1 sumoylation
    Chungsik Choi
    Department of Physiology, College of Medicine, University of South Alabama, Mobile, Alabama 36609, USA
    Am J Physiol Heart Circ Physiol 299:H1660-70. 2010
  4. ncbi Myosin phosphatase regulatory pathways: different functions or redundant functions?
    Thomas M Lincoln
    Circ Res 100:10-2. 2007

Scientific Experts

  • Shuxia Wang
  • Thomas M Lincoln
  • Sukrutha Chettimada
  • Chungsik Choi
  • Zachary Simms
  • Sachin A Gupte
  • Robert Kobelja
  • Nupur Dey
  • Michael S Wolin
  • Dhwajbahadur K Rawat
  • Felricia M Brown
  • Hassan Sellak

Detail Information

Publications4

  1. pmc Glc-6-PD and PKG contribute to hypoxia-induced decrease in smooth muscle cell contractile phenotype proteins in pulmonary artery
    Sukrutha Chettimada
    Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
    Am J Physiol Lung Cell Mol Physiol 303:L64-74. 2012
    ..The present findings indicate that increases in Glc-6-PD activity influence PKG activity and smooth muscle cell phenotype proteins, all of which affect pulmonary artery contractility and remodeling...
  2. pmc Glucose downregulation of PKG-I protein mediates increased thrombospondin1-dependent TGF-{beta} activity in vascular smooth muscle cells
    Shuxia Wang
    Univ of Kentucky, Lexington, 40536, USA
    Am J Physiol Cell Physiol 298:C1188-97. 2010
    ..Together, these data establish that glucose-mediated downregulation of PKG levels stimulates TSP1 expression and enhances TGF-beta activity and matrix protein expression, which can contribute to vascular remodeling in diabetes...
  3. pmc cGMP-dependent protein kinase and the regulation of vascular smooth muscle cell gene expression: possible involvement of Elk-1 sumoylation
    Chungsik Choi
    Department of Physiology, College of Medicine, University of South Alabama, Mobile, Alabama 36609, USA
    Am J Physiol Heart Circ Physiol 299:H1660-70. 2010
    ..Taken together, these data suggest that PKG-I decreases Elk-1 activity by sumo modification of Elk-1, thereby increasing myocardin-SRF activity on SMC-specific gene expression...
  4. ncbi Myosin phosphatase regulatory pathways: different functions or redundant functions?
    Thomas M Lincoln
    Circ Res 100:10-2. 2007