Von Willebrand factor (vWF) is a procoagulant that is expressed specifically in endothelial cells (ECs) and megakaryocytes. Preliminary studies demonstrate several interesting features of vWF gene regulation. First, vWF is preferentially expressed in veins compared with arteries and exposure of cultured ECs to venous flow results in higher expression of vWF expression compared with arterial flow. Second. vWF expression in ECs from different organs is mediated by distinct DNA promoter elements. Third, sepsis is associated with increased circulating levels of vWF protein, yet widespread repression of vWF transcription, an effect that may be explained by reduced transcriptional activity of the ETS factors, ERG. Based upon this background, the overall hypothesis is that vWF expression is spatially and temporally regulated by mechanisms that involve hemodynamic forces, vascular bed/organ-specific transcriptional modules and the ETS factor.
Aim 1 will test the hypothesis that arterial-venous differences in vWF expression are mediated by flow.
Aim 2 will test the hypothesis that the vWF promoter contains c/s-regulatory elements that direct vascular bed-specific gene expression in the capillaries and veins of heart and skeletal muscle.
Aim 3 will test the hypothesis that the repression of vWF in endotoxemia is mediated by ERG activity.
The overall significance of these studies is that they will provide new insights into mechanisms of EC heterogeneity and lay a foundation for vascular bed-specific targeting. Experiments in Aim 1 are significant because they will provide new insights into the plasticity of the endothelium and the role of flow in mediating differential gene expression. Studies in Aim 2 are significant in that they will extend our observations related to the modular regulation of vWF expression. Finally, Aim 3 will yield important information about spatial and temporal regulation of EC gene expression in sepsis, which is a prevalent pathophysiological condition in humans.
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