Disintegrin Metalloprotease (ADAM) 10 Regulates Endothelial Permeability and T Cell Transmigration by Proteolysis of Vascular Endothelial Cadherin

• Published in: Circulation research Vol. 102; no. 10; pp. 1192 - 1201
• Main Authors: Schulz, Beate, Pruessmeyer, Jessica, Maretzky, Thorsten, Ludwig, Andreas, Blobel, Carl P., Saftig, Paul, Reiss, Karina
• Format: Journal Article
• Language: English
• Published: 17.04.2008
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.107.169805

Vascular endothelial (VE)-cadherin is the major adhesion molecule of endothelial adherens junctions. It plays an essential role in controlling endothelial permeability, vascular integrity, leukocyte transmigration, and angiogenesis. Elevated levels of soluble VE-cadherin are associated with diseases like coronary atherosclerosis. Previous data showed that the extracellular domain of VE-cadherin is released by an unknown metalloprotease activity during apoptosis. In this study, we used gain of function analyses, inhibitor studies and RNA interference experiments to analyze the proteolytic release of VE-cadherin in human umbilical vein endothelial cells (HUVECs). We found that VE-cadherin is specifically cleaved by the disintegrin and metalloprotease ADAM10 in its ectodomain releasing a soluble fragment and generating a carboxyterminal membrane bound stub, which is a substrate for a subsequent γ-secretase cleavage. This ADAM10-mediated proteolysis could be induced by Ca 2+ -influx and staurosporine treatment, indicating that ADAM10-mediated VE-cadherin cleavage contributes to the dissolution of adherens junctions during endothelial cell activation and apoptosis, respectively. In contrast, protein kinase C activation or inhibition did not modulate VE-cadherin processing. Increased ADAM10 expression was functionally associated with an increase in endothelial permeability. Remarkably, our data indicate that ADAM10 activity also contributes to the thrombin-induced decrease of endothelial cell-cell adhesion. Moreover, knockdown of ADAM10 in HUVECs as well as in T cells by small interfering RNA impaired T cell transmigration. Taken together our data identify ADAM10 as a novel regulator of vascular permeability and demonstrate a hitherto unknown function of ADAM10 in the regulation of VE-cadherin-dependent endothelial cell functions and leukocyte transendothelial migration.