Differing biological activities of mouse angiopoietin-3 as compared with human angiopoietin-4. Angiopoietin chimeras containing the angiopoietin-4 fibrinogen-like domain activate Tie2 receptors in either human (A) or mouse (B) endothelial cells as well as in mouse fibroblasts (C), whereas angiopoietin chimeras containing the angiopoietin-3 fibrinogen-like domain cannot activate Tie2 receptors in either human (A) or mouse (B) endothelial cells, although they can in mouse fibroblasts (C). Furthermore, excess amounts of chimeras containing the angiopoietin-3 fibrinogen-like domain can blunt the ability of angiopoietin-1 to activate the Tie2 receptor (D). Thus, whereas angiopoietin-4 derivatives act as agonists (like angiopoietin-1), angiopoietin-3 derivatives act as context-dependent antagonists (like angiopoietin-2).