Received for publication March 18, 2005.
Revised April 28, 2005.
Accepted for publication April 28, 2005.

ANGIOPOIETIN-2 CAUSES INFLAMMATION IN VIVO BY PROMOTING VASCULAR LEAKAGE

Abstract

Angiopoietins (Ang) are endothelium-selective ligands that exert their actions through the Tie-2 receptor. It is widely accepted that 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 experimental conditions. To define the role of Ang-2 in acute inflammation we studied the effects of recombinant Ang-2 administration in vivo. Here we show that Ang-2, but not Ang-1, induces edema formation in the mouse paw in a dose-dependent manner: the edema appears fast peaking at 30 min and resolves within 4hr. The effect of Ang-2 is blocked by co-administration with a soluble form of the Tie-2 receptor or Ang-1. Nitric oxide and PGE₂ levels in mouse paw following injection of Ang-2 remained unaltered, suggesting that the action of Ang-2 does not involve these mediators. In addition, Ang-2 exerted a weak stimulatory effect on leukocyte migration in the mouse paw. Similarly, Ang-2 injected into the mouse air pouch produced only a modest effect on cell extravasation that peaked at 30 min. However, when cell migration was elicited using zymosan, Ang-2 significantly inhibited leukocyte migration. We conclude that Ang-2 by itself stimulates the extravasation of cell-poor fluid, but in presence of ongoing inflammation reduces cellular infiltration in tissues.

Key words: angiopoietin, endothelium, inflammation, permeability, tie2, vascular endothelial growth factor

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