Endothelial barrier function is integral to the homeostasis of any tissue of the human body. The paracellular space between neighboring endothelial cells is sealed by specialized junctions that prevent the passage of fluids, ions, molecules and cells. A breach of this barrier can have serious consequences. Local activation of endothelial cells in response to injury increases vascular permeability at this site. Generalized activation of the endothelium as seen in sepsis causes extensive vascular leak and leads to life-threatening conditions. Barrier function for fluid and small molecules is safeguarded by tight junctions. They consist of transmembrane proteins and a dense cytoplasmic plaque of proteins linking the transmembrane complex to the cytoskeleton and to signaling complexes. The cytoplasmic adaptor protein cingulin binds junctional adhesion molecules, zonula occludens proteins, components of the cytoskeleton, and RhoGTPase exchange factors. Its multiple interaction domains suggest that this protein participates in the regulation of tight junction adhesiveness. However, so far, the role of cingulin in endothelial tight junctions is unknown. For the first time, cingulin could be identified as a component of endothelial tight junctions. Moreover, I demonstrated that cingulin regulates endothelial permeability in vitro and in vivo. Consequently, I used a therapeutic peptide mimicking a highly conserved motif within the cingulin molecule, which is required to interact with zonula occludens proteins. In cell culture, a core structure consisting of 11 amino acids proved sufficient to reduce the formation of stress fibres in endothelial cells. In a mouse model of local burn injury, this cingulin-derived peptide reduced the nonperfused area after 12days. Furthermore, in a complex model of orthotopic lung transplantation in rats, the peptide significantly decreased lung edema and preserved lung morphology compared to the control group. In summary, I could show that the adaptor protein cingulin is a component of endothelial tight junctions that contributes to the regulation of endothelial permeability in vivo and in vitro.