Signaling and functions of angiopoietin-1 in vascular protection

Abstract

Angiopoietin-1 (Ang1) has powerful vascular protective effects: suppressing plasma leakage, inhibiting vascular inflammation, and preventing endothelial death. Preclinical studies indicate that Ang1 may be therapeutically useful in a number of situations, including treatment of edema, endotoxemia, and transplant arteriosclerosis. However, the ligand has also been implicated in vessel remodeling, induction of angiogenesis and pulmonary hypertension, indicating that strategies to minimize any deleterious effects while optimizing vessel protection are likely to be needed. This review surveys the published data on vascular protective effects of Ang1 and highlights the therapeutic potential of this ligand, as well as possible limitations to its use. We also consider the data on Ang1 receptors and speculate on how to maximize therapeutic benefit by targeting the Tie receptors.

Figure 1. Angiopoietin-1 signalling

Schematic representation of established and potential signalling pathways activated by Ang1 in endothelial cells. Key phosphotyrosines are shown for the carboxy-terminus of Tie2 and cellular functions regulated by Ang1 are indicated towards the bottom of the figure. The domain structure of Tie2 is very similar to the related Tie1 receptor tyrosine kinase. Tie2 is the well established transducer of Ang1 signals, but recent data indicates that Tie1 is also activated by Ang1. Furthermore, heteromeric complexes between Tie1 and Tie2 were detected in cells expressing both receptors. However, possible signalling emanating from these heteromeric receptor complexes remains to be defined. Integrins have been found to interact with both Ang1 and Tie2, but the importance of these interactions on Tie2 signalling are largely unknown. Other details of the receptors, signalling intermediates and functions are given in the text. The top left corner of the figure depicts the structural features of human Ang1 together with approximate amino acid residue number flanking each domain. Following the secretory leader sequence (S) is the superclustering domain (SCD), coiled-coil domain (CCD), hinge region (H) and fibrinogen-related domain (FReD).