Functional inhibition of secreted angiopoietin: a novel role for angiopoietin 1 in coronary vessel patterning

The angiopoietins are a family of growth factors critical for development and maintenance of the vasculature. The primary amino acid sequence of the angiopoietins predicts that they are comprised of a coiled–coiled and a fibrinogen-like domain. The coiled–coiled domain mediates ligand multimerizatio...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2004-10, Vol.323 (3), p.937-946
Main Authors: Ward, Nicole L., Slyke, Paul Van, Dumont, Daniel J.
Format: Article
Language:English
Subjects:
Angiogenesis
Angiopoietin-1 - genetics
Angiopoietin-1 - metabolism
Angiopoietin-2 - genetics
Angiopoietin-2 - metabolism
Animals
Cell migration
Cell Movement - physiology
Cloning, Molecular
Coronary vessels
Coronary Vessels - cytology
Coronary Vessels - metabolism
Dimerization
Endothelial Cells - cytology
Endothelial Cells - physiology
Endothelial growth factors
Humans
Mice
Mice, Transgenic
Neovascularization, Physiologic - physiology
Protein Binding
Receptor phosphorylation
Receptor, TIE-2 - metabolism
Recombinant Proteins - metabolism
Signal Transduction - physiology
Structure-Activity Relationship
Transgenic
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Summary:The angiopoietins are a family of growth factors critical for development and maintenance of the vasculature. The primary amino acid sequence of the angiopoietins predicts that they are comprised of a coiled–coiled and a fibrinogen-like domain. The coiled–coiled domain mediates ligand multimerization, whereas the fibrinogen domain engages the receptor. This multimerization is required to elicit a ligand-mediated biological effect via activation of their receptor Tie2. In vitro and in vivo knockout studies have suggested that the angiopoietins are chemotactic for endothelial cells. We were interested in ascertaining whether the angiopoietins have this activity within the animal proper. To accomplish this we engineered a dominant-interfering form of angiopoietin (Ang) 1, called Ang1cc. Ang1cc contains the coiled–coiled domain, which can heterodimerize with other angiopoietins produced in the same cell. We show that Ang1cc can inhibit Tie2 activation and can inhibit Ang1 activity in vitro and in vivo.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2004.08.185