The mechanism of endothelial cell specific gene expression of Von Willebrand Factor in vivo

Abstract

In vivo analyses of the Von Willebrand Factor (VWF) promoter previously demonstrated that a fragment spanning sequences -487 to +247 targets promoter activation to brain vascular endothelial cells. This fragment is active in all embryonic vessels of transgenic mice but in adult mice its activity is restricted to brain vascular endothelial cells, while endogenous VWF gene is expressed in vasculature of all major organs. In this study we demonstrate that a DNase I hypersensitive (HSS) sequences in intron 51 of the VWF gene contain cis-acting elements that are necessary for the VWF gene transcription in a subset of lung endothelial cells in vivo. Our results demonstrated that Nuclear Factor 1 (NF1) and Nuclear transcription Factor Y (NFY) repressors contribute to VWF organ-specific regulation. Mutation of the NF1 binding site resulted in promoter activation in lung and heart, while mutation of the repressor corresponding to a novel binding site for NFY resulted in promoter activation in kidney vasculature.