Vascular smooth muscle cells (SMCs), the major cellular constituent of an artery, synthesize of the bulk of the connective tissue of the vessel wall, including elastin and the fibrillar collagens type I and V/XI. In response to injury and in certain disease states such as atherosclerosis, normally quiescent medial SMCs migrate to the intima where they undergo proliferation, and deposit matrix components, thereby contributing to formation of an atherosclerotic plaque and to vessel occlusion. Importantly, mounting evidence indicates that rupture of the fibrous cap of the plaque leads to thromboembolic complications in atherosclerotic coronary and carotid artery disease. Cytomegalovirus (CMV) infection has been implicated as a contributing agent in the pathogenesis of atherosclerosis, as well as in restenosis. Work in the PI's lab has led to the hypothesis that the myb and NF-kappaB families of transcription factors play key roles in coordinated control of matrix synthesis and proliferation of the vascular SMC. B-Myb was found to repress SMC type I and V collagen and elastin gene transcription in culture and phosphorylation by cyclin A/cdk2 relieved repression of the alpha2(V) collagen promoter. A transgenic mouse model carrying the B-myb transgene was recently created; the aortae and isolated SMCs of the transgenic mice were found to display a large decrease in elastin and substantially reduced collagen and lysyl oxidase mRNA expression compared to wild type mice. While B-myb gene expression is regulated by SMC growth state, c-Myb and A-Myb were shown to promote vascular SMC proliferation. Furthermore, the CMV immediate early (IE) 1 protein was found to selectively induce RelB/p50 NF-kappaB complexes, which may control transcription of genes that promote SMC proliferation. Here, four aims are proposed to elucidate the roles of Myb and NF-kappaB factors in cardiovascular disease: Aim 1. Determine the effects of ectopic expression of B-Myb on lesion formation as a result of femoral artery injury. To elucidate the effects of a high fat diet, the B-myb transgenic mice will be crossbred with an ApoE knockout mouse to place B-Myb overexpression within the context of an ApoE -/ background. The effects of B-Myb expression on matrix deposition, lesion formation, and geometric remodeling of the vessel wall will be evaluated; Aim 2. Elucidate the mechanism of transcriptional repression of elastin gene expression by B-Myb; Aim 3. Elucidate the mechanism whereby cyclin A phosphorylation ablates the ability of B-Myb to repress matrix gene expression; Aim 4. Elucidate the mechanism of NF-kappaB RelB subunit activation by CMV IE1 protein and its role in transactivation of genes that control cell proliferation. These studies should provide important new information on control of two critical mediators in cardiovascular disease: vascular SMC proliferation and matrix production.