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New soluble angiopoietin analog of Hepta‐ANG1 prevents pathological vascular leakage
- Source :
- Biotechnology and Bioengineering. 118:423-432
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
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.
- Subjects :
- 0106 biological sciences
0301 basic medicine
Recombinant Fusion Proteins
Bioengineering
Vascular permeability
vascular perme
01 natural sciences
Applied Microbiology and Biotechnology
Angiopoietin
Mice
03 medical and health sciences
chemistry.chemical_compound
Protein Domains
Sepsis
010608 biotechnology
Angiopoietin-1
Human Umbilical Vein Endothelial Cells
Animals
Humans
Vascular Diseases
chimeric protein
Mice, Inbred BALB C
Respiratory Distress Syndrome
biology
Complement C4b-Binding Protein
angiopoietin‐Tie2 pathway
Fusion protein
Angiopoietin receptor
Cell biology
Vascular endothelial growth factor
HEK293 Cells
030104 developmental biology
chemistry
angiopoetin 1
biology.protein
Phosphorylation
Female
Rabbits
Signal transduction
Tyrosine kinase
Biotechnology
Subjects
Details
- ISSN :
- 10970290 and 00063592
- Volume :
- 118
- Database :
- OpenAIRE
- Journal :
- Biotechnology and Bioengineering
- Accession number :
- edsair.doi.dedup.....8a5156945cecfb506ab0318b98d86b6e