Molecular mechanisms of endothelial cell–cell adhesion and barrier function are not fully understood. IGPR-1 is a novel CAM expressed in ECs and is localized to endothelial adherens junctions. IGPR-1through trans-homophilic dimerization regulates endothelial cell–cell adhesion and barrier. Trans-homophilic dimerization of IGPR-1 stimulates the phosphorylation of Ser220, which is required for IGPR-1 to stimulate endothelial barrier function and angiogenesis.