Angiopoietin-2 increases endothetial permeability in vivo

Angiopoietins (Ang) are endothelium-selective ligands that exert their actions through the Tie-2 receptor. The best-studied Ang so far, Ang-1, promotes structural integrity of blood vessels and exhibits anti-inflammatory properties. In contrast, the role of Ang-2 remains less clear, as it has been shown to behave as a Tie-2 agonist or antagonist under different conditions. To better define the role of Ang-2 in vascular permeability and inflammation, we studied the effects of recombinant Ang-2 administration in models of acute inflammation. In the mouse hind paw, Ang-2 stimulated edema formation in a dose-dependent manner that was maximal 30 min after the injection and returned to baseline after 4hr. This effect of Ang-2 could be blocked by co-administration of a soluble form of the Tie-2 receptor. On the other hand, Ang-1 did not alter paw volume when used alone, but abolished Ang-2-stimulated edema. In the same model, the effect of submaximal Ang-2 and vascular endothelial growth factor (VEGF) doses was additive; however, using high Ang-2 and VEGF doses did not further promote edema formation. Measurements in the exudates revealed that Ang-2 did not alter nitric oxide and PGE ₂ production in tissues and only weakly stimulated leukocyte migration in the mouse paw. A weak stimulatory effect of Ang-2 on cell margination was also observed in the air pouch model; however, Ang-2 inhibited zymosan-induced leukocyte migration in this model. We conclude that Ang-2 stimulates the passage of cell-poor fluid through the endothelium, but inhibits cellular infiltration in tissues in response to inflammatory stimuli.