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1 Cardiovascular Research Institute, Comprehensive Cancer Center, Department of Anatomy, University of California, San Francisco, San Francisco, California, USA
2 Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA
* To whom correspondence should be addressed. E-mail: dmcd{at}itsa.ucsf.edu.
Angiopoietin-1 (Ang1) is essential for remodeling of the primitive vascular plexus and recruitment of mural cells during embryonic development. In the adult vasculature, Ang1 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 anti-leak effect of Ang1 in the airways of mice. Intravenous injection of bradykinin resulted in leakage of fluorescent microspheres (diameter 25 to 1000 nm) from tracheal venules. The leakage peaked in 3 to 4 minutes and resolved by 10 minutes. High-resolution confocal microscopy revealed the presence of focal gaps at intercellular junctions of leaky venules. Genetically engineered Ang1 (Ang1*), 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 Ang1 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.
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