Journal
BIOMATERIALS
Volume 51, Issue -, Pages 119-128Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2015.01.062
Keywords
Angiogenesis; Tie2 receptor; Angiopoietin-1; Agonistic antibody
Funding
- National Research Foundation of Korea - Ministry of Science, Information & Communication Technology and Future Planning [NRF-2012M3A9C6050331, NRF-2012M3A9C7050101, NRF-2014M3A9C4066458]
- Creative Allied Project (CAP) through the National Research Council of Science and Technology (NST)
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Angiopoietin-1 (Angl) and its endothelium-specific receptor, tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2), play critical roles in vascular development. Although the Ang1/Tie2 system has been considered a promising target for therapeutic neovascularization, several imitations of large-scale production have hampered the development of recombinant Angl for therapeutics. In this study, we produced a fully human agonistic antibody against Tie2, designated 1-4h, and tested the applicability of 1-4h as an alternative to native Ang1 in therapeutic angiogenesis. 1-4h significantly enhanced the phosphorylation of Tie2 in a dose- and time-dependent manner in human Tie2-expressing HEK293 cells and human umbilical vein endothelial cells. Moreover, 1-4h induced the activation of Tie2-mediated intracellular signaling such as AKT, eNOS, MAPK, and Focal Adhesion Kinase p125(FAK). In addition, 1-4h increased the chemotactic motility and capillary-like tube formation of endothelial cells in vitro and enhanced the survival of serum-deprived endothelial cells. Taken together, our data clearly suggest that a human Tie2 agonistic antibody is a potentially useful therapeutic approach for the treatment of several ischemic diseases including delayed-wound healing and ischemic heart and limb diseases. (C) 2015 Elsevier Ltd. All rights reserved.
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