Abstract: It has been discovered that phosphorylation-dependent uncoupling of endothelial nitric oxide synthase (eNOS) plays an important role in endothelial cell (EC) barrier disruption. Compositions and methods to reduce or prevent eNOS uncoupling are disclosed. Decoy peptides that can prevent phosphorylation and mitochondrial redistribution of eNOS, reduce eNOS uncoupling, and preserve EC barrier function, and uses thereof, are described. The peptides improve lung vascular integrity in a mouse model of VILI. Thus, the decoy peptides can be used to treat or prevent diseases or disorders associated with increased vascular permeability such as ALI, ARDS, and VILI.