Vascular endothelial cadherin (VE-cadherin), which is localized at adherent junctions, is involved in the control of vascular permeability. A growing body of evidence indicates that NO modulates the movement of fluid and proteins out of the vasculature. In this paper, we investigated whether NO can disrupt the VE-cadherin complex. We found that treatment with two NO donors (SIN-1 and SNAP) markedly reduced the amount of VE-cadherin in a murine microvascular endothelial cell line (H5V) as demonstrated by immunoprecipitation analysis, cellular ELISA, and Northern blot analysis. beta- and gamma-Catenins were also found to be affected by the two NO donors. Moreover, the disruption of the complex, induced by NO donors, correlated with increases in vascular permeability using both in vivo and in vitro models. These results clearly demonstrate a role for NO in vascular permeability. (C) 2003 Elsevier Science (USA). All rights reserved.