Endotoxemia is characterized by multiple dysfunctions of the micro-vascular endothelium. Of these, vascular leakage is an initial event that aggravates vascular dysfunction can lead to systemic vascular collapse and organ failure. Thus, prevention of vascular leakage may ameliorate endotoxin-induced dysfunctions of blood vessels. Here we examine the effect of an angiopoietin-1 variant, COMP-Ang1, on endotoxin-induced vascular leakage in mice. COMP-Ang1 significantly reduced endotoxin-induced vascular leakage in the lung, heart, and kidney, but not in liver or intestine. Interestingly, COMP-Ang1 attenuated endotoxin-induced lung damage, presumably due to reduced infiltration of macrophages. Moreover, COMP-Ang1 restored the level of PECAM-I expression, which is significantly reduced by endotoxin challenge. This study suggests that COMP-Ang1 reduces endotoxin-induced vascular leakage by restoration of cellular junctions and subsequent attenuation of leukocyte infiltration. (C) 2009 Elsevier Inc. All rights reserved.