Biological characterization of angiopoietin‐3 and angiopoietin‐4

Abstract

The angiopoietin (Ang) family of growth factors includes Ang1, Ang2, Ang3, and Ang4, all of which bind to the endothelial receptor tyrosine kinase Tie2. Ang3 (mouse) and Ang4 (human) are interspecies orthologs. In experiments with human endothelial cell lines, Ang3 was identified as an antagonist of Tie2 and Ang4 was identified as an agonist of Tie2. However, the biological roles of Ang3 and Ang4 are unknown. We examined the biological effect of recombinant Ang3 and Ang4 proteins in primary cultured endothelial cells and in vivo in mice. Recombinant Ang3 and Ang4 formed disulfide-linked dimers. Ang4 (400 ng/mL) markedly increased Tie2 and Akt phosphorylation in primary cultured HUVECs whereas Ang3 (400 ng/mL) did not produce significant changes. Accordingly, Ang4, but not Ang3, induced survival and migration in primary cultured HUVECs. Unexpectedly, intravenously administered Ang3 (30 microg) was more potent than Ang4 (30 microg) in phosphorylating the Tie2 receptor in lung tissue from mice in vivo. Accordingly, Ang3 was more potent than Ang4 in phosphorylating Akt in primary cultured mouse lung microvascular endothelial cells. Ang3 and Ang4 both produced potent corneal angiogenesis extending from the limbus across the mouse cornea in vivo. Thus, Ang3 and Ang4 are agonists of Tie2, but mouse Ang3 has strong activity only on endothelial cells of its own species.

Angiopoietin: A TIE(d) Balance in Tumor Angiogenesis

“…ANG-2 (25) and its isoform (125) are believed to be natural antagonists of the TIE-2 pathway. ANG-3 and ANG-4 are believed to be species orthologues in mouse and human, respectively (63), which regulate TIE-2 in a species-specific manner (65). The coiled-coil domain is involved in the multimerization of the ligands and the fibrinogen-like domain functions as the receptor-binding motif.…”

“…TIE-2/TIE-1 heterodimerization is known to inhibit ANG-2 activation of the receptor (73). ANG-3 and ANG-4 are able to activate TIE-2 receptor in a species-specific manner (65). The integrin a 5 h 1 and a v h 5 receptors may transduce ANG-1 and ANG-2 signals independent of TIE-2 (32, 76, 77), but they may also work synergistically with TIE-2 receptor (131).…”

Roles of Angiopoietins in Kidney Development and Disease

“…[1][2][3][4] During normal development, they are considered critical for vascular differentiation through angiogenesis, the process of growth and remodeling of existing vessels; they are also involved in the maintenance and turnover of blood vessels in late gestation and in mature animals. [1][2][3]5 Ang-1 and Ang-2 are ligands for the Tie-2 (tyrosine kinase with Ig and EGF homology domain 2) receptor tyrosine kinase, which is characteristically expressed by blood endothelial cells. Ang-1 oligomers and multimers bind to and tyrosine-phosphorylate Tie-2 through their COOH-terminal fibrinogen-like domains, causing enhanced endothelial survival and endothelial cell-cell stabilization.…”

Morphogens and blood-brain barrier function in health and disease

“…Both are agonists of the Tie-2 receptor. 91 While the role of angiopoietins in angiogenesis has been established for a long time, we have only begun to discover their involvement in neurogenesis in the last few years. Ang-1 was shown to promote neurogenesis in adult brain after cerebral ischemia 92 while Ang-2 is involved in the developing telencephalon as well as in adult neurogenesis.…”