Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage.
Angiopoietins (Angs) are endothelium-selective ligands that exert most of their actions through the Tie-2 receptor. It is widely accepted that Ang-1 promotes the structural integrity of blood vessels and exhibits anti-inflammatory properties. In contrast, the role of Ang-2 remains less clear because 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. We show herein that Ang-2, but not Ang-1, induces edema formation in the mouse paw in a dose-dependent manner; the edema seems to be fast-peaking (maximum at 30 min) and resolves within 4 h. The effect of Ang-2 is blocked by the coadministration with a soluble form of the Tie-2 receptor or Ang-1. NO and prostaglandin E(2) levels in mouse paw following the 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 the presence of ongoing inflammation it reduces cellular infiltration in tissues.
Roviezzo
Fiorentina
F
Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece 26504.
Tsigkos
Stelios
S
Kotanidou
Anastasia
A
Bucci
Mariarosaria
M
Brancaleone
Vincenzo
V
Cirino
Giuseppe
G
Papapetropoulos
Andreas
A
D042683:Angiopoietin-1 / Q000494:pharmacology; D042702:Angiopoietin-2 / Q000494:pharmacology*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology*; D002199:Capillary Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005122:Exudates and Transudates / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology*; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D004791:Enzyme Inhibitors; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D015054:Zymosan; D009195:Peroxidase; D042787:Receptor, TIE-2; D015232:Dinoprostone