The formation of new blood vessels is termed "angiogenesis" and occurs by a process in which new vessels "sprout" from preexisting ones. Impairment of this process leads to delayed wound healing and chronic ulcers, while an uncontrolled, excessive angiogenic response contributes to the growth and spread of tumors. The endothelial cells that line the microvessels of the circulation are the central cellular actors during angiogenesis. Increased understanding of the processes involved in angiogenesis (such as the migration of endothelial cells) has led to the recognition that the interactions of endothelial cells with the proteins in the matrix around the cells (extracellular matrix), and the receptors that mediate these interactions, are of critical importance to the formation of new blood vessels. One of the molecules on endothelial cells that appears to be involved in this process is PECAM-1. A role of PECAM-1 in angiogenesis is supported by the fact that vessel formation is impaired by anti-PECAM-1 antibodies and in PECAM-1-deficient mice. We hypothesize that PECAM-1 facilitates endothelial cell motility by modulating endothelial cell interactions with the extracellular matrix. The successful completion of the studies in this proposal will further our understanding of the mechanisms that regulate the formation of vessels and may potentially provide new directions for the development of therapeutic agents targeting angiogenesis. As angiogenesis is essential for wound healing following tissue injury, as well as for tumor growth and metastasis, the proposed studies are very relevant not only to personnel currently in the military but to older, retired service people who seek cancer-related treatments through the VA Medical Centers.