Endothelium plays an important role in the regulation of the cardiovascular system. Situated between the circulating components of the blood and underlying smooth muscle cells, the products of endothelial genes can be critical determinants in the pathophysiology of the vessel wall. For example, in atherosclerosis secretory products produced by dysfunctional endothelium might initiate the migration and proliferation of smooth muscle cells characteristic of the lesion. 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 transgenic mouse models in which the endothelial cell selectively over-expresses these proteins. However, development of appropriate transgenic models requires endothelial-specific expression of these mediators. In the proposed studies, we will characterize the endothelial-leukocyte adhesion molecule-1 gene that is selectively expressed by endothelial cells and define the regulatory elements that confer endothelial-specific gene expression. In parallel we will characterize the vascular cell adhesion molecule-1 gene which is efficiently expressed in all types of cytokine-activated endothelium. The putative DNA binding protein(s) responsible for the endothelial-specific transcriptional control process will be defined. This information will assist us in designing expression constructs 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 pathobiology of the vessel wall. 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.
