Vascular endothelium forms a multifunctional interface between the circulating blood and the peripheral tissues. It is a metabolically active component of the vessel wall, serving as a source of multiple factors that are important for normal homeostasis. Endothelial cells can undergo adaptive changes in function that are critical to normal physiological processes and the pathogenesis of vascular disease. The underlying assumption behind these studies has been that a crucial initial step in endothelial dysfunction consists of increased production of platelet-derived growth factor (PDGF) by endothelium. Regulation of PDGF expression by endothelial cells occurs in part at the transcriptional level. Exploring the structure of the PDGF A- and B-chain genes and their transcriptional regulation by endothelial cells has been a focus of this laboratory for the past ten years. We have suggested a role for Sp1 and the immediate early growth response transcription factor (Egr-1) in the regulation of these genes. There is growing evidence that Egr-1 orchestrates the transcriptional response to vascular injury and may play a key pathogenic role in atherosclerosis. In the renewal period, we propose to characterize the coactivators, corepressors and chromatin remodeling factors that interact with Egr-1 and affect its ability to regulate transcription. Additionally, we will determine the role of EgM expressed either by endothelial or smooth muscle cells in animal models of atherosclerosis and vascular injury and characterize the role of the Egr-1 corepressors NAB1 and NAB2 during development and possibly in the pathobiology of the vessel wall. These studies should better define the molecular mechanisms regulating PDGF gene expression and provide new insights into the role of Egr-1 as a pathogenic transcription factor in the vessel wall. Collectively, the studies should provide new strategies for the management of vascular disease. ? ? ?
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