Figure.

Role of ADAM-10 in leukocyte recruitment and transmigration and endothelial cell permeability. In activated endothelium, upregulated cell adhesion molecules such as fractalkine, CXCL16 and hyaluronan ( ) bind their respective receptors CX3CR1, CXCR6 and CD44 (Y) resulting in initial capture of inflammatory cells. Inflammatory mediators such as thrombin (acting via protease-activated receptor, PAR), and leukocyte adhesion increase endothelial cell [Ca²⁺]_i, causing the release of pro-ADAM-10 from calmodulin (CAM) and activation of ADAM-10. Activated ADAM-10 cleaves the adhesion molecules resulting in leukocyte deadhesion, initial rolling and subsequent migration to inter-endothelial junction. The released ectodomains act as soluble chemokines to further recruit inflammatory cells to the endothelium. Activated ADAM-10 also cleaves VE-cadherin ectodomain resulting in endothelial cell gap formation and inflammatory cell transmigration. The remaining membrane bound stub of VE-cadherin is cleaved by Ca²⁺-sependent γ-secretase leading to the release of β-catenin, α-catenin and actin from the plasma membrane and alterations in cell morphology and nuclear signaling.