Regulation of Endothelial Cell Function in Angiogenesis

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Angiogenesis is the proliferation of new blood vessels from pre-existing vasculature. It is a complex process which requires that the endothelial cell dissociate from underlying basement membrane, initiate a proliferative program, migrate toward a stimulus, and then exit the cell cycle, renew attachment to extracellular matrix, and re-establish inter- cellular junctions forming a functional three-dimensional tubular array. This program project will focus on the dynamic behaviors of the endothelial cell which characterize its participation in the "angiogenic switch" and which lead dynamic behaviors of the endothelial cell which characterize its participation in the "angiogenic switch" and which lead to formation of a stable conduit for flowing blood. We plan four closely interdigitating projects each of which addresses a novel aspect of the angiogenic endothelial cell phenotype. Project 1 will examine the molecular mechanism by which the endothelial cell acquires cell surface proteolytic in the form of the serine protease, plasmin. Newly developed annexin II null mice and annexin II promoter-LacZ transgenic mice will be employed to define the requirement for annexin II, as well as its regulation by the atherothrombotic amino acid, homocysteine, in several angiogenesis, thrombospondin-1, interacts with its cell surface receptor CD36 and activates a signaling pathway. Recently developed CD36 null mice will serve as a unique reagent for examining this system in angiogenesis. Project 3 will address the identification and characterization of a unique G-protein coupled receptor that mediates the angiogenesis effects of the CXC class of chemokines. This project will investigate the co-stimulatory requirements of the receptor, a putative heterodimer, as well as its ligands and intracellular signaling proteins. Project 4 will consider the mobilization and recruitment of bone marrow- derived endothelial progenitor cells and their participation in angiogenesis during the wound healing and other neovascular responses. All four projects will make extensive use of three support facilities. An Administrative Core will provide budgetary, secretarial, and organization support services to the program. A Histotechnology Core will supply technical expertise and practical assistance with tissue procurement, processing, and imaging. An Animal Models Core will provide a series of in vivo model systems for the analysis of processing, and imaging. An Animals Models Core will provide a series of in vivo model systems for the analysis of angiogenesis in mice. In summary, we believe that the projects and cores of this program embody a dynamic, interactive, and productive program that, with strong institutional support, will succeed in elucidating new mechanisms and paradigms to enlighten our understanding of angiogenic processes.