| DOI | Resolve DOI: https://doi.org/10.1002/bit.27580 |
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| Author | Search for: Liu, PanORCID identifier: https://orcid.org/0000-0002-3066-652X; Search for: Ryczko, Michael; Search for: Xie, Xinfang; Search for: Baardsnes, Jason1; Search for: Lord‐Dufour, Simon1; Search for: Duroche, Yves1; Search for: Hicks, Emily Anne; Search for: Taiyab, Aftab; Search for: Sheardown, Heather; Search for: Quaggin, Susan E.; Search for: Jin, Jing |
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| Affiliation | - National Research Council of Canada. Human Health Therapeutics
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| Funder | Search for: National Institutes of Health |
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| Format | Text, Article |
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| Subject | angiopoetin 1; angiopoietin‐Tie2 pathway; chimeric protein; vascular perme |
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| Abstract | Vascular leak is a key driver of organ injury in diseases, and strategies that reduce enhanced permeability and vascular inflammation are promising therapeutic targets. Activation of the angiopoietin-1 (ANG1)-Tie2 tyrosine kinase signaling pathway is an important regulator of vascular quiescence. Here we describe the design and construction of a new soluble ANG1 mimetic that is a potent activator of endothelial Tie2 in vitro and in vivo. Using a chimeric fusion strategy, we replaced the extracellular matrix (ECM) binding and oligomerization domain of ANG1 with a heptameric scaffold derived from the C-terminus of serum complement protein C4-binding protein α. We refer to this new fusion protein biologic as Hepta-ANG1, which forms a stable heptamer and induces Tie2 phosphorylation in cultured cells, and in the lung following intravenous injection of mice. Injection of Hepta-ANG1 ameliorates vascular endothelial growth factor- and lipopolysaccharide-induced vascular leakage, in keeping with the known functions of Angpt1-Tie2 in maintaining quiescent vascular stability. The new Hepta-ANG1 fusion is easy to produce and displays remarkable stability with high multimericity that can potently activate Tie2. It could be a new candidate ANG1 mimetic therapy for treatments of inflammatory vascular leak, such as acute respiratory distress syndrome and sepsis. |
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| Publication date | 2020-09-24 |
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| Publisher | Wiley |
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| In | |
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| Language | English |
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| Peer reviewed | Yes |
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| Export citation | Export as RIS |
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| Report a correction | Report a correction (opens in a new tab) |
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| Record identifier | 29c15f39-f7a3-45c6-a33b-80d74a107e37 |
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| Record created | 2023-02-20 |
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| Record modified | 2023-02-20 |
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