Oxidized Phospholipids and Angiogenesis

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DESCRIPTION (Applicant's abstract) Dr. Karol Watson is a physician/scientist with a research background in both atherosclerosis and angiogenesis who is developing a research program that combines the two fields. Her long-term career goals are to become a productive, independent investigator in the field of atherosclerosis associated angiogenesis. Because of the rapid developments in the fields of both angiogenesis and atherosclerosis additional research training and career development will be essential to her future. The Environment: The environment at UCLA is ideal for this career development. Dr. Watson has been assured, protected research time that will allow her to spend 80% of her time in research, a fully equipped laboratory and access to all of the equipment and expertise in the laboratories of her mentors and advisors. The Research: Angiogenesis is the complex process by which new capillary blood vessels are generated from existing microvessels. Many proteins which modulate angiogenesis have been identified, and in the past few years, lipid mediators have also been studied. It is the study of potential lipid mediators of angiogenesis (namely oxidized phospholipid mediators) which forms the basis for the current proposal. Low density lipoprotein (LDL)- derived oxidized phospholipids are important in the development of athero- sclerosis. Emerging evidence from this laboratory suggests that these oxidized phospholipids may also act as mediators of angiogenesis. The major objectives of this proposal are to clarify the role of these lipid oxidation products in stimulating angiogenesis in vivo, and to investigate the role of monocyte/macrophages in the process. The overall hypothesis of this grant is that lipid oxidation products induce angiogenesis in vivo via: a) attraction of monocyte/macrophages, and b) stimulation of monocyte/macrophages to produce potent angiogenic factors such as VEGF. To address this hypothesis this following specific aims have been established: 1) To determine the effects of monocyte/macrophage products on in vitro angiogenesis in the presence of oxidized phospholipids. 2) To test the hypothesis that systemic lipid oxidation products cause monocyte/macrophages to upregulate secretion of VEGF and stimulate angiogenesis in vivo. 3) To test the hypothesis that macrophages are necessary for oxidized phospholipid-induced angiogenesis by performing angiogenesis assays in macrophage-deficient mice. Information derived from these experiments will contribute to understanding the role of lipid oxidation products in angiogenesis, and potentially explain the co- localization of atherosclerosis and angiogenesis in vivo.