Endothelial cells are positioned between the circulating components of the blood and the underlying smooth muscle cells of the vascular wall. In this strategic location, the products of endothelial genes can be critical determinants of pathologic reactions. For example, in hypertension, the ability of the endothelium to produce relaxing factors is blunted, while its ability to produce contracting factors is increased. Study of the protein mediators involved in these processes would be facilitated by production of a transgenic mouse model in which the endothelial cell selectively over-expresses these proteins. However, development of an appropriate transgenic model requires endothelial-specific expression of these mediators. In the proposed studies, the promoter of a gene whose expression is restricted to endothelial cells will be characterized and the elements responsible for endothelial-specific gene expression will be defined. Additionally, the endothelial proteins responsible for the transcriptional control of endothelial-specific genes will be identified. This information will assist us in designing transgenes which will selectively target expression of exogenous genes to the endothelial cell in the transgenic mouse model. By genetically manipulating the endothelium, it may be possible to determine what role this cell plays in the pathogenesis of hypertensive vascular disease. Furthermore, characterization of both the cis-elements and transacting factors responsible for endothelial-specific gene expression may permit the development of new strategies for identifying patients at risk of vascular disease.
