Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules

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Abstract
Angiopoietin-1 (Ang-1) is essential for remodeling of the primitive vascular plexus and recruitment of mural cells during embryonic development. In the adult vasculature, Ang-1 can reduce plasma leakage in inflammation, but the mechanism of this action is not well understood. In the present study, we determined the magnitude and cellular mechanism of the antileak effect of Ang-1 in the airways of mice. Intravenous injection of bradykinin resulted in leakage of fluorescent microspheres (diameter 25–1,000 nm) from tracheal venules. The leakage peaked in 3–4 min and resolved by 10 min. High-resolution confocal microscopy revealed the presence of focal gaps at intercellular junctions of leaky venules. Genetically engineered Ang-1*, delivered systemically by adenoviral transduction of the liver, reduced leakage of 500-nm microspheres after bradykinin by 69%. The reduction in leakage coincided with a decrease in number and size of endothelial gaps. The proportion of venular surface occupied by endothelial gaps decreased 61%. Microsphere leakage correlated strongly with gap number and size ( r2 = 0.89). Together the results suggest that Ang-1 reduces leakage from inflamed venules by restricting the number and size of gaps that form at endothelial cell junctions through effects on intracellular signaling, cytoskeleton, and junction-related molecules.