Endothelial cell activation/injury are initiating events in atherogenesis. This disease and its attendant complications such as thrombosis represent the major cause of mortality in this country. This renewal application, consisting of six scientific components and two core facilities, sets specific objectives to define the mechanisms involved in the pathogenesis of thrombo-atherosclerosis.. Through active collaboration, we will test the hypothesis that soluble mediators (e.g nitrogen oxides, reactive species, growth factors), and vascular cells to elucidate the signals governing functional and metabolic properties of the circulatory system. Particular emphasis will be placed on: the effects of fluid-phase and cell- associated thromboregulators (ectoADPase); NO; eicosanoids) on vascular and blood cell reactivity; modulation of cardiovascular stress responses by annexin II; the mechanisms by which the type B scavenger receptor, CD36; modulates vascular cell signaling; specific intracellular pathways mediating arterial cell migration and cytoskeleton reorganization; a molecular explanation of nitric oxide insufficiency in atherogenesis; and, studies on modulation of cycloooxygenase by nitrogen oxides and specific signalling cascades associated with vascular disease. The overall program is designed to utilize the complementary research expertise of our vascular biology group to promote synergistic interactions. We take pride that during the past 10 years, this has occurred.. Our on-going collaborative efforts, where our PPG Vascular Biology group has published 96 peer-reviewed original basic research papers during the past 4 years, coupled with our major scientific discoveries, underscores the success of this program. As a testament to our achievements, Cornell Medical School established a Center of Vascular Biology headed by Dr. David Hajjar. Institutional funds (>$1.0 million) are ear-marked for capital improvements, new equipment, and faulty development to help support this program.