Journal article
ADAM10 Regulates Endothelial Permeability and T-Cell Transmigration by Proteolysis of Vascular Endothelial Cadherin
Circulation research, Vol.102(10), pp.1192-1201
05/23/2008
DOI: 10.1161/CIRCRESAHA.107.169805
PMID: 18420943
Abstract
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 carboxyl-terminal membrane-bound stub, which is a substrate for a subsequent γ-secretase cleavage. This ADAM10-mediated proteolysis could be induced by Ca 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.
Details
- Title: Subtitle
- ADAM10 Regulates Endothelial Permeability and T-Cell Transmigration by Proteolysis of Vascular Endothelial Cadherin
- Creators
- Beate Schulz - From the Biochemical Institute (B.S., P.S., K.R.), Christian-Albrecht-University Kiel, Germany; Institute of Molecular Cardiovascular Research (J.P., A.L.), RWTH Aachen, Germany; and Arthritis and Tissue Degeneration Program (T.M., C.P.B.), Hospital for Special Surgery, Weill Medical College of Cornell University, New YorkJessica PruessmeyerThorsten MaretzkyAndreas LudwigCarl BlobelPaul SaftigKarina Reiss
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.102(10), pp.1192-1201
- DOI
- 10.1161/CIRCRESAHA.107.169805
- PMID
- 18420943
- NLM abbreviation
- Circ Res
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Publisher
- American Heart Association, Inc
- Language
- English
- Date published
- 05/23/2008
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984094542502771
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