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 tong-term goal of this project has been to elucidate cellular and molecular mechanisms that control the growth and differentiation of SMC during vascular development, and to determine how these control processes are altered during phenotypic switching of SMC in association with vascular injury and disease. A key to understanding these processes is to identify environmental cues (or factors) that influence the differentiated state of SMC and to determine mechanisms and signaling pathways whereby these factors alter expression of genes required for the differentiated function of the SMC. The focus of studies in this proposal is to test the hypothesis that the SMC selective SRF co-activator myocardin or myocardin- like factors function as a point of convergence for regulation of SMC gene expression in response to both positive and negative regulators of SMC differentiation such as angiotensin II (A-II) and PDGF BB respectively and that these factors exert their effects at least in part by histone dependent modifications in chromatin structure that influence binding of SRF-myocardin to CArG elements within SMC promoter-enhancers.
Aim 1 will determine the role and mechanisms by which PDGF BB regulates differentiation of vascular SMC and will include determining the role of KLF4, Sp1/3, and chromatin modifications in PDGF BB induced suppression of SMC marker genes (Aim 1a), as well as determining effects of SMC targeted knockout of the PDGF beta-receptor or KLF4 on SMC maturation during development, and phenotypic switching following vascular injury or ApoE -/- experimental atherogenesis in vivo (Aim 1b).
Aim 2 will determine the molecular mechanisms whereby A-II and other contractile agonists promote expression of SMC marker genes including testing the hypothesis that effects are mediated in part through increased expression and/or recruitment of myocardin-SRF (or MAL-SRF) to degenerate CArG elements contained within the promoters of virtually all SMC marker genes, as well as through rho kinase dependent mechanisms. The proposed studies involve extensive interactions with each Project within this Program Project. 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.
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