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 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.
Ward
Nicole L
NL
Division of Molecular and Cellular Biology Research, Sunnybrook and Women's Research Institute, Toronto, Ontario, Canada M4N 3M5.
Van Slyke
Paul
P
Dumont
Daniel J
DJ
D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D003001:Cloning, Molecular; D003331:Coronary Vessels / Q000166:cytology* / Q000378:metabolism*; D019281:Dimerization; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011485:Protein Binding; D042787:Receptor, TIE-2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D011994:Recombinant Proteins; D042787:Receptor, TIE-2