Cardiovascular diseases (CVDs) are the leading cause of death throughout the world. Elevated Low Density Lipoprotein (LDL) is a well-known cardiovascular risk factor and endothelial (ECs)-lipoprotein (LIPs) interactions underlie the initiation and progression of atherogenesis, thrombosis and other CVDs.The endothelium is a monolayer of cells that segregates the vascular contents from adjacent tissues. In spite of being continually exposed to LIPs, ECs were long thought of as inert barriers, through which lipids are exchanged between plasma and surrounding tissues. In contrast to this view, recent work from my laboratory has uncovered a deleterious role of ApoB-LIPs as direct inhibitors of angiogenesis in the developing embryo. These findings present only the tip of the iceberg, and the underlying cellular and molecular mechanisms are largely unknown. In this proposal, we will tackle this question by undertaking three independent but complementary approaches, aimed at characterizing LIP-EC interactions at a different level: cellular, molecular or pathological. We will explore these facets in zebrafish and mammals, utilizing live imaging, sophisticated lipidomic and biochemical analyses, as well as tumor xenografts and genetic mutants. An important and unique aspect of our approach is the focus on in vivo dynamics, in contrast to the extensive body of literature on LIP effects on cultured ECs. When completed this proposal will have shed light on a little explored, but critical aspect in the etiology of CVDs. Furthermore it will provide answers to important unresolved questions: What are the signaling pathways activated in ECs upon LIP binding? How are LIPs transported within ECs? Does ApoB possess additional functions beyond that of cholesterol carrier? Can high LIPs levels inhibit tumor angiogenesis and metastasis? In a broader sense, a deeper understanding of the effects of LIPs on ECs will be valuable for identifying new targets for therapeutic intervention.