New soluble angiopoietin analog of Hepta‐ANG1 prevents pathological vascular leakage

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. He...

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Bibliographic Details
Published in:Biotechnology and bioengineering Vol. 118; no. 1; pp. 423 - 432
Main Authors: Liu, Pan, Ryczko, Michael, Xie, Xinfang, Baardsnes, Jason, Lord‐Dufour, Simon, Duroche, Yves, Hicks, Emily Anne, Taiyab, Aftab, Sheardown, Heather, Quaggin, Susan E, Jin, Jing
Format: Journal Article
Language:English
Published: United States Wiley 01.01.2021
Wiley Subscription Services, Inc
Subjects:
angiopoetin 1
Angiopoietin
Angiopoietin-1 - biosynthesis
Angiopoietin-1 - genetics
Angiopoietin-1 - pharmacology
angiopoietin‐Tie2 pathway
Animals
chimeric protein
Complement C4b-Binding Protein - biosynthesis
Complement C4b-Binding Protein - genetics
Complement C4b-Binding Protein - pharmacology
Complement component C4
Extracellular matrix
Female
Fusion protein
Growth factors
HEK293 Cells
Human Umbilical Vein Endothelial Cells - metabolism
Humans
Inflammation
Injection
Injury prevention
Intravenous administration
Kinases
Leakage
Lipopolysaccharides
Mice
Mice, Inbred BALB C
Oligomerization
Permeability
Phosphorylation
Protein Domains
Protein-tyrosine kinase
Proteins
Rabbits
Recombinant Fusion Proteins - biosynthesis
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - pharmacology
Respiratory distress syndrome
Respiratory Distress Syndrome - drug therapy
Respiratory Distress Syndrome - metabolism
Respiratory Distress Syndrome - pathology
Sepsis
Sepsis - drug therapy
Sepsis - metabolism
Sepsis - pathology
Signal transduction
Stability
Tyrosine
Vascular Diseases - drug therapy
Vascular Diseases - metabolism
Vascular Diseases - pathology
Vascular endothelial growth factor
vascular perme
vascular permeability
angiopoetin 1
vascular permeability
angiopoietin-Tie2 pathway
chimeric protein
ISSN:1097-0290, 0006-3592, 1097-0290
Online Access:Get full text
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Summary: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.
NRC publication: Yes
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ISSN:1097-0290
0006-3592
1097-0290
DOI:10.1002/bit.27580