Alterations in the differentiated state of the smooth muscle cell (SMC) play a key role in the development and/or progression of a variety of cardiovascular diseases. The goal of this project is to elucidate the role and mechanisms whereby transforming growth factor beta (TGFbeta) signaling pathways control SMC differentiation-maturation during vascular development, as well as during vascular injury in adult animals. The underlying hypothesis is that TGFbeta signaling pathways play a critical role in the initial induction of SMC differentiation marker genes during early vascular development, as well as in sustained expression of these genes in cells already committed to the SMC lineage. Moreover, we hypothesize that the effects of TGFbeta are mediated at least in part through TGFbeta control element (TCE)/TCE binding factor (TCEBF)-dependent pathways identified in our previous studies in cultured cells, and that these processes are also important in controlling alterations in expression of SMC marker genes following vascular injury. We will test these hypotheses by addressing three specific aims.
Aim 1 is to define the role of TGFbeta signaling pathways in control of SMC differentiation and maturation in vivo during vascular development, and in in vitro models of early SMC differentiation. Studies will include determining: 1) the spatial-temporal expression patterns of TGFbeta1, and TGFbeta receptors during initial investment of blood vessels with presumptive SMC; 2) if inhibition of TGFbeta1 signaling pathways blocks differentiation of multipotential cells to SMC lineages in vitro; and 3) if SMC specific abrogation of TGFbeta signaling using our unique SMC specific mouse gene targeting system inhibits SMC differentiation-maturation in vivo.
Aim 2 is to determine molecular mechanisms whereby TGFbeta1 stimulates expression of SMC differentiation marker genes. Studies will test if effects of TGFbeta1 are mediated through TCEBFs (e.g. BTEB2 and GKLF) identified in our yeast one-hybrid screens, and will include determining: 1) expression patterns of TCEBFs during vasculogenesis; 2) effects of SMC-targeted knockout or over- expression of TCEBFs in vivo; and 3) if effects of TCEBFs involve interactions with TGFbeta SMAD signaling proteins.
Aim 3 is to determine the role of TGFbeta signaling mechanisms in control of SMC growth and phenotypic modulation following vascular injury in vivo. Studies will use a novel transgenic mouse injury model developed in our lab, and include determining the effects of SMC targeted knockout of GKLF and TGFbeta receptor signaling pathways. Taken together, studies will provide key insights regarding cellular/molecular mechanisms that control differentiation of SMC, and contribute to understanding the role these processes might play in development of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL038854-19
Application #
6899858
Study Section
Pathology A Study Section (PTHA)
Program Officer
Srinivas, Pothur R
Project Start
1987-07-01
Project End
2006-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
19
Fiscal Year
2005
Total Cost
$329,178
Indirect Cost
Name
University of Virginia
Department
Physiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Baylis, Richard A; Gomez, Delphine; Owens, Gary K (2017) Shifting the Focus of Preclinical, Murine Atherosclerosis Studies From Prevention to Late-Stage Intervention. Circ Res 120:775-777
Murgai, Meera; Ju, Wei; Eason, Matthew et al. (2017) KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nat Med 23:1176-1190
Shankman, Laura S; Gomez, Delphine; Cherepanova, Olga A et al. (2016) Corrigendum: KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med 22:217
Cherepanova, Olga A; Gomez, Delphine; Shankman, Laura S et al. (2016) Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nat Med 22:657-65
Gomez, Delphine; Owens, Gary K (2016) Reconciling Smooth Muscle Cell Oligoclonality and Proliferative Capacity in Experimental Atherosclerosis. Circ Res 119:1262-1264
Gomez, Delphine; Swiatlowska, Pamela; Owens, Gary K (2015) Epigenetic Control of Smooth Muscle Cell Identity and Lineage Memory. Arterioscler Thromb Vasc Biol 35:2508-16
Gomez, Delphine; Shankman, Laura S; Nguyen, Anh T et al. (2013) Detection of histone modifications at specific gene loci in single cells in histological sections. Nat Methods 10:171-7
Leeper, Nicholas J; Raiesdana, Azad; Kojima, Yoko et al. (2013) Loss of CDKN2B promotes p53-dependent smooth muscle cell apoptosis and aneurysm formation. Arterioscler Thromb Vasc Biol 33:e1-e10
Salmon, Morgan; Gomez, Delphine; Greene, Elizabeth et al. (2012) Cooperative binding of KLF4, pELK-1, and HDAC2 to a G/C repressor element in the SM22? promoter mediates transcriptional silencing during SMC phenotypic switching in vivo. Circ Res 111:685-96
Alexander, Matthew R; Moehle, Christopher W; Johnson, Jason L et al. (2012) Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice. J Clin Invest 122:70-9

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