The vascular endothelium plays a critical role in regulation of vascular tone, vessel growth, proliferation of smooth muscle, hemostasis, vasculogenesis and angiogenesis. However, little is known about the mechanisms of gene regulation that underlie these events. Endothelin-1 (ET-1), a potent vasoconstrictor peptide, is expressed predominantly in an endothelial cell-specific fashion, and its expression is tightly regulated both in health and in disease. Based on my preliminary data, I propose that VEZFl/DB1, a zinc finger transcription factor, is an endothelial cell-specific transcription factor that regulates the expression of ET-1. I have characterized the participation of VEZFl/DB1 in DNA:protein complexes at the minimal VEZF1/DB1 response element (cis-acting element) in the ET-1 promoter. I intend to test the importance of this element in developmental expression of ET- 1 gene using transgenic mice containing a promoter construct mutated at this site. I will also identify and characterize potential interacting partners that participate with VEZFI/DB1 in regulating the expression of ET-1 gene via a yeast two-hybrid screen, and test the importance of these interaction partners on ET-1 expression. These studies should provide important new insight into the mechanisms underlying endothelial gene expression in health and disease.
