title: The recombinant lectin-like domain of thrombomodulin inhibits angiogenesis through interaction with Lewis Y antigen.
abstract: Lewis Y Ag (LeY) is a cell-surface tetrasaccharide that participates in angiogenesis. Recently, we demonstrated that LeY is a specific ligand of the recombinant lectin-like domain of thrombomodulin (TM). However, the biologic function of interaction between LeY and TM in endothelial cells has never been investigated. Therefore, the role of LeY in tube formation and the role of the recombinant lectin-like domain of TM-TM domain 1 (rTMD1)-in antiangiogenesis were investigated. The recombinant TM ectodomain exhibited lower angiogenic activity than did the recombinant TM domains 2 and 3. rTMD1 interacted with soluble LeY and membrane-bound LeY and inhibited soluble LeY-mediated chemotaxis of endothelial cells. LeY was highly expressed on membrane ruffles and protrusions during tube formation on Matrigel. Blockade of LeY with rTMD1 or Ab against LeY inhibited endothelial tube formation in vitro. Epidermal growth factor (EGF) receptor in HUVECs was LeY modified. rTMD1 inhibited EGF receptor signaling, chemotaxis, and tube formation in vitro, and EGF-mediated angiogenesis and tumor angiogenesis in vivo. We concluded that LeY is involved in vascular endothelial tube formation and rTMD1 inhibits angiogenesis via interaction with LeY. Administration of rTMD1 or recombinant adeno-associated virus vector carrying TMD1 could be a promising antiangiogenesis strategy.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National ChengKung University, 1 University Road, Tainan, Taiwan.
authors.forename: Cheng-Hsiang
authors.initials: CH
authors.lastname: Kuo
authors.forename: Po-Ku
authors.initials: PK
authors.lastname: Chen
authors.forename: Bi-Ing
authors.initials: BI
authors.lastname: Chang
authors.forename: Meng-Chen
authors.initials: MC
authors.lastname: Sung
authors.forename: Chung-Sheng
authors.initials: CS
authors.lastname: Shi
authors.forename: Jeng-Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Chuan-Fa
authors.initials: CF
authors.lastname: Chang
authors.forename: Guey-Yueh
authors.initials: GY
authors.lastname: Shi
authors.forename: Hua-Lin
authors.initials: HL
authors.lastname: Wu
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000637:transplantation; D006801:Humans; D037102:Lectins / Q000737:chemistry; D007983:Lewis Blood Group Antigens / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D018180:Thrombomodulin / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D037102:Lectins; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D011994:Recombinant Proteins; D018180:Thrombomodulin