Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology

Abstract

Angiopoietins 1-4 (Ang1-4) represent an important family of growth factors, whose activities are mediated through the tyrosine kinase receptors, Tie1 and Tie2. The best characterized are angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2). Ang1 is a potent angiogenic growth factor signaling through Tie2, whereas Ang2 was initially identified as a vascular disruptive agent with antagonistic activity through the same receptor. Recent data demonstrates that Ang2 has context-dependent agonist activities. Ang2 plays important roles in physiological processes and the deregulation of its expression is characteristic of several diseases. In this review, we summarize the activity of Ang2 on blood and lymphatic endothelial cells, its significance in human physiology and disease, and provide a current view of the molecular signaling pathways regulated by Ang2 in endothelial cells.

Keywords: Tie1; Tie2; angiogenesis; angiopoietin-2; cancer; endothelial cells; inflammation; integrin.

Figure 1

Schematic representation of the Ang2 effect on the vascular bed in normal conditions, inflammation, and cancer. Under normal physiological conditions, Ang2 levels are low, but are upregulated during inflammation or cancer. Ang2 acts on endothelial cells, increasing endothelial permeability and also on the pericytes, causing pericyte detachment from the basement membrane, further inducing vascular leakiness, immune or/and cancer cell trans-endothelial migration, and deterioration of the condition. Ang2 has been proposed as a marker for inflammatory conditions and cancer.

Figure 2

Illustration of the main signaling pathways activated upon Ang2 binding to endothelial cells. Ang2 can interact with Tie2 either as an antagonist or as an agonist, when present at high concentrations. Activation of the Tie2 downstream pathway, which occurs in the absence of VE-PTP, eventually leads to Foxo1 inhibition and upregulation of endothelial functions. Upon Ang2 binding, Tie2 heterodimerizes with Tie1 and they can both form complexes with integrins. Ang2 can bind to integrins also independently of Tie2, inducing endothelial cell migration and sprout formation.