Vascular smooth muscle cells (SMCs) synthesize the bulk of the matrix proteins within the medial layer of major arteries and are responsible for the deposition of matrix proteins that occlude blood flow within the intima in an atherosclerotic plaque. We have recently demonstrated that B- myb, a member of the myb family of transcription factors, is expressed by the SMC in a cell cycle dependent fashion, and that B-myb negatively regulates promoter activity of the genes encoding the two type I collagen chains and the alpha2 chain and lysyl oxidase (LO) promoters, in collaboration with J. Foster and H. Kagan, respectively. Since B-myb expression was high in actively proliferating SMCs, and decreased as cell growth slowed, negative regulation of matrix gene expression by B-myb may represent an important component of the inverse relationship previously observed between matrix production and growth of vascular SMCs.
Four specific aims are proposed to provide additional characterization of B-myb expression in SMCs and to begin to elucidate the mechanism of B-myb down- regulation of matrix expression and to evaluate the role of this negative effector on in vivo matrix gene expression.
Aim 1 : characterize the effects on B-myb expression of cell density treatment of SMCs with basic fibroblast growth factor (bFGF) or modulation of cAMP levels.
Aim 2 : localize promotor and possible intronic sequences mediating B-myb down- regulation of type I collagen, elastin and LO gene transcription.
Aim 3 : elucidate the mechanism of B-myb down-regulation of matrix gene transcription using the alpha2(V) collagen gene as paradigm.
Aim 4 : determine the functional role of B-myb expression in the vessel wall using a transgenic mouse model. These studies should shed light on the expression of B-myb and the role of this transcription factor in control of matrix production and formation of the normal vessel wall. Lastly, these findings should provide valuable insights into vascular disease involving excess matrix deposition and proliferation by the SMC, including atherosclerosis and restonosis.
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