Figure 1.

A schematic model of the angiopoietin-Tie2 ligand-receptor system. Quiescent endothelial cells are attached to pericytes that constitutively produce Ang-1. As a vascular maintenance factor, Ang-1 reacts with the endothelial tyrosine kinase receptor Tie2. Ligand binding to the extracellular domain of Tie2 results in receptor dimerization, autophosphorylation, docking of adaptors and coupling to intracellular signalling pathways. Signal transduction by Tie2 activates the PI3K/Akt cell survival signalling pathway, thereby leading to vascular stabilization. Tie2 activation also inhibits the NF-κB-dependent expression of inflammatory genes, such as those encoding luminal adhesion molecules (for example, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin). Ang-2 is stored and rapidly released from WPBs in an autocrine and paracrine fashion upon stimulation by various inflammatory agents. Ang-2 acts as an antagonist of Ang-1, stops Tie2 signalling, and sensitizes endothelium to inflammatory mediators (for example, tumour necrosis factor-α) or facilitates vascular endothelial growth factor-induced angiogenesis. Ang-2-mediated disruption of protective Ang-1/Tie2 signalling causes disassembly of cell-cell junctions via the Rho kinase pathway. In inflammation, this process causes capillary leakage and facilitates transmigration of leucocytes. In angiogenesis, loss of cell-cell contacts is a prerequisite for endothelial cell migration and new vessel formation. Ang, angiopoietin; NF-κB, nuclear factor-κB; PI3K, phosphoinositide-3 kinase; WPB, Weibel-Palade body.