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Le^y/H: An Endothelial-Selective, Cytokine-Inducible, Angiogenic Mediator¹

Margaret M. Halloran^*, William W. Carley^§, Peter J. Polverini^||, Catherine J. Haskell^*, Stacie Phan^§, Byron J. Anderson, James M. Woods^*, Phillip L. Campbell^*, Michael V. Volin^*, Annika E. Bäcker^¶ and Alisa E. Koch^2,*,

^* Department of Medicine, Section of Arthritis and Connective Tissue Diseases, and Department of Cellular and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611; Veterans Administration Chicago Health Care System, Lakeside Division, Chicago, IL 60611; ^§ Bayer Corp., West Haven, CT 06516; ^¶ Department of Laboratory Medicine, Sahlgrenska Hospital, Goteborg, Sweden; and ^|| Laboratory of Molecular Pathogenesis, University of Michigan Dental School, Ann Arbor, MI 48108

Endothelial cells (ECs) are key participants in angiogenic processes that characterize tumor growth, wound repair, and inflammatory diseases, such as human rheumatoid arthritis (RA). We and others have shown that EC molecules, such as soluble E-selectin, mediate angiogenesis. Here we describe an EC molecule, Lewis^y-6/H-5-2 glycoconjugate (Le^y/H), that shares some structural features with the soluble E-selectin ligand, sialyl Lewis^x (sialyl Le^x). One of the main previously recognized functions of Lewis^y is as a blood group glycoconjugate. Here we show that Le^y/H is rapidly cytokine inducible, up-regulated in RA synovial tissue, where it is cell-bound, and up-regulated in the soluble form in angiogenic RA compared with nonangiogenic osteoarthritic joint fluid. Soluble Le^y/H also has a novel function, for it is a potent angiogenic mediator in both in vitro and in vivo bioassays. These results suggest a novel paradigm of soluble blood group Ags as mediators of angiogenic responses and suggest new targets for therapy of diseases, such as RA, that are characterized by persistent neovascularization.