The phenotypic plasticity of vascular smooth muscle cells (SMCs) permits this muscle cell lineage to subserve diverse functions including the maintenance of arterial tone via contraction- relaxation and vessel wall integrity by proliferation and synthesis of extracellular matrix. By differentially regulating the expression of distinct sets of SMC lineage-specific genes, SMCs can modulate their phenotype from primarily contractile to primarily synthetic. However, relatively little is currently understood about the molecular mechanisms that control SMC-specific gene expression. One approach to understanding the molecular mechanisms that regulate SMC differentiation is to identify and characterize the cis-acting sequences and trans-acting factors that control SMC-specific transcription. Because of its SMC lineage-restricted pattern of expression, we have used the murine SM22alpha gene as a model system to examine the mechanisms that control SMC-specific gene expression. Preliminary studies demonstrated that SM22alpha is one of the earliest developmental markers of the SMC lineage. Moreover, the 280-bp SM22alpha promoter directs arterial SMC lineage-restricted gene expression in transgenic mice. This transcriptional regulatory element contains previously undescribed nuclear protein binding sites that bind lineage-restricted trans-acting factors. These data support the hypothesis that novel SMC lineage- restricted transcription factors control the expression of the SM22alpha gene in SMCs. The proposed studies are designed to elucidate the molecular mechanisms that control the SMC-specific pattern of SM22alpha gene.
The specific aims of these studies are to: (i) identify the cis-acting elements that control activity for the arterial SMC-specific SM22alpha promoter during embryonic and postnatal development, (ii) characterize the trans-acting factors that regulate expression of the SM22alpha gene, (iii) examine the molecular mechanisms underlying activity of positive and negative regulatory factors on SM22alpha promoter activity, and (iv) clone and characterize SMC-specific transcription factors that regulate activity of the SM22alpha gene in SMCs should fundamentally increase understanding of SMC development and differentiation. As such, the proposed studies are relevant to understanding the pathogenesis of atherosclerosis and restenosis following balloon angioplasty.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL056915-03
Application #
2832592
Study Section
Pathology A Study Section (PTHA)
Project Start
1997-04-01
Project End
2001-03-31
Budget Start
1998-07-01
Budget End
1999-03-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Li, Jian; Zhu, Xiaohong; Chen, Mary et al. (2005) Myocardin-related transcription factor B is required in cardiac neural crest for smooth muscle differentiation and cardiovascular development. Proc Natl Acad Sci U S A 102:8916-21
Abdullah, Ibrahim; Lepore, John J; Epstein, Jonathan A et al. (2005) MRL mice fail to heal the heart in response to ischemia-reperfusion injury. Wound Repair Regen 13:205-8
Lepore, John J; Cappola, Thomas P; Mericko, Patricia A et al. (2005) GATA-6 regulates genes promoting synthetic functions in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 25:309-14
Proweller, Aaron; Pear, Warren S; Parmacek, Michael S (2005) Notch signaling represses myocardin-induced smooth muscle cell differentiation. J Biol Chem 280:8994-9004
Ding, Rubai; Darland, Diane C; Parmacek, Michael S et al. (2004) Endothelial-mesenchymal interactions in vitro reveal molecular mechanisms of smooth muscle/pericyte differentiation. Stem Cells Dev 13:509-20
Du, Kevin L; Ip, Hon S; Li, Jian et al. (2003) Myocardin is a critical serum response factor cofactor in the transcriptional program regulating smooth muscle cell differentiation. Mol Cell Biol 23:2425-37
Kim, S; Lin, H; Barr, E et al. (1997) Transcriptional targeting of replication-defective adenovirus transgene expression to smooth muscle cells in vivo. J Clin Invest 100:1006-14
Kim, S; Ip, H S; Lu, M M et al. (1997) A serum response factor-dependent transcriptional regulatory program identifies distinct smooth muscle cell sublineages. Mol Cell Biol 17:2266-78