title: A Designed Angiopoietin-1 Variant, Dimeric CMP-Ang1 Activates Tie2 and Stimulates Angiogenesis and Vascular Stabilization in N-glycan Dependent Manner.
abstract: Angiopoietin-1 (Ang1), a potential growth factor for therapeutic angiogenesis and vascular stabilization, is known to specifically cluster and activate Tie2 in high oligomeric forms, which is a unique and essential process in this ligand-receptor interaction. However, highly oligomeric native Ang1 and Ang1 variants are difficult to produce, purify, and store in a stable and active form. To overcome these limitations, we developed a simple and active dimeric CMP-Ang1 by replacing the N-terminal of native Ang1 with the coiled-coil domain of cartilage matrix protein (CMP) bearing mutations in its cysteine residues. This dimeric CMP-Ang1 effectively increased the migration, survival, and tube formation of endothelial cells via Tie2 activation. Furthermore, dimeric CMP-Ang1 induced angiogenesis and suppressed vascular leakage in vivo. Despite its dimeric structure, the potencies of such Tie2-activation-induced effects were comparable to those of a previously engineered protein, COMP-Ang1. We also revealed that these effects of dimeric CMP-Ang1 were affected by specified N-glycosylation in its fibrinogen-like domain. Taken together, our results indicate that dimeric CMP-Ang1 is capable of activating Tie2 and stimulating angiogenesis in N-glycan dependent manner.
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.|Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.
authors.forename: Nuri
authors.initials: N
authors.lastname: Oh
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.|Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.
authors.forename: Kangsan
authors.initials: K
authors.lastname: Kim
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.
authors.forename: Intae
authors.initials: I
authors.lastname: Park
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.|Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Korea.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Seo
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Korea.
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: An
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.
authors.forename: Ho Min
authors.initials: HM
authors.lastname: Kim
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.|Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D064235:Matrilin Proteins / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011134:Polysaccharides / Q000378:metabolism*; D011487:Protein Conformation; D055503:Protein Multimerization; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000819:agonists* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D042683:Angiopoietin-1; D064235:Matrilin Proteins; D011134:Polysaccharides; D011993:Recombinant Fusion Proteins; D042787:Receptor, TIE-2; D051057:Proto-Oncogene Proteins c-akt