Angiogenesis, or new blood vessel growth, is an important process in conditions such as atherosclerosis, tumor growth, and rheumatoid arthritis (RA). We have shown previously that interleukin-8 is a potent macrophage-derived mediator of angiogenesis (Koch, et al, Science 258: 1798, 1992). We have also shown that soluble endothelial cell adhesion molecules soluble E-selectin (sE-selectin), and soluble vascular cell adhesion molecule-1 can function in a manner similar to cytokines in inducing angiogenesis (Koch, et al, Nature 376:517, 1995). We demonstrated that the mechanism by which sE-selectin mediates angiogenesis is via its endothelial ligand sialyl-Lewis (sialyl-Lex). Currently, we focus on a novel endothelial (EC) molecule, 4A11, detected by monoclonal antibody (mAb) 4A11 produced in our laboratory. This antigen is virtually endothelial-specific, as well as endothelial selective, being expressed mainly on EC in normal synovium, lymphoid tissues, thymus, and skin, suggesting a possible role in cell homing to these areas. The 4A11 antigen is cytokine-inducible in vitro and is upregulated in human RA synovial tissue lining affected joints and in a human poison ivy model of contact dermatitis. Moreover, the antigen detected by monoclonal antibody 4A11 is contained in both Lewisy-6 (Ley) and H-5-2 (H-2). Ley is within the new family of carbohydrates which includes sialyl-Lex, the sE-selectin ligand through which the sE- selectin mediates angiogenesis. We have recently found that the soluble 4A11 antigen mediates angiogenesis.
The aim of this proposal is to determine the mechanism by which the 4A11 antigen mediates angiogenesis and participates in cell adhesion, and the role of the 4A11 antigen in disease. We propose to confirm the angiogenic activity of the 4A11 antigen using in vitro and in vivo angiogenesis assays. We will determine whether the 4A11 antigen mediates upregulation of EC adhesion molecules and EC or leukocyte adhesion. We will characterize the role of this antigen in disease. Since the synthesis of the 4A11 antigen is regulated by fucosyltransferases, we will examine whether a defect in angiogenesis occurs in """"""""knockout"""""""" mice deficient in fucosyltransferase. We will determine whether these mice have decreased corneal angiogenesis, wound repair, expression of other angiogenic mediators, or angiogenic arthritic responses compared to parental controls. These studies should broaden our understanding of the mode of action of this novel angiogenic mediator which may increase our ability to curb angiogenesis in conditions characterized by persistent neovascularization.
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