This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 102/10/1192    most recent CIRCRESAHA.107.169805v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schulz, B. Articles by Reiss, K. Search for Related Content PubMed PubMed Citation Articles by Schulz, B. Articles by Reiss, K. Related Collections Cell biology/structural biology Thrombin Endothelium/vascular type/nitric oxide Other Vascular biology Related Article

(Circulation Research. 2008;102:1192.)
© 2008 American Heart Association, Inc.

Molecular Medicine

ADAM10 Regulates Endothelial Permeability and T-Cell Transmigration by Proteolysis of Vascular Endothelial Cadherin

Beate Schulz^*, Jessica Pruessmeyer^*, Thorsten Maretzky, Andreas Ludwig, Carl P. Blobel, Paul Saftig, Karina Reiss

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 York.

Correspondence to Karina Reiss, Biochemical Institute; Christian-Albrecht-University Kiel, Olshausenstr. 40, D-24098 Kiel, Germany. E-mail k.reiss{at}biochem.uni-kiel.de

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 -secretase cleavage. This ADAM10-mediated proteolysis could be induced by Ca²⁺ 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.

Key Words: endothelium • metalloprotease • endothelial permeability • VE-cadherin

Related Article:

Role of ADAMs in Endothelial Cell Permeability: Cadherin Shedding and Leukocyte Rolling

Bharathy Ponnuchamy and Raouf A. Khalil
Circ. Res. 2008 102: 1139-1142. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				S. E. Byeseda, A. R. Burns, S. Dieffenbaugher, R. E. Rumbaut, C. W. Smith, and Z. Li ICAM-1 Is Necessary for Epithelial Recruitment of {gamma}{delta} T Cells and Efficient Corneal Wound Healing Am. J. Pathol., August 1, 2009; 175(2): 571 - 579. [Abstract] [Full Text] [PDF]

				J. I. Borissoff, H. M.H. Spronk, S. Heeneman, and H. ten Cate Is thrombin a key player in the 'coagulation-atherogenesis' maze? Cardiovasc Res, June 1, 2009; 82(3): 392 - 403. [Abstract] [Full Text] [PDF]

				R. R. Koenen, J. Pruessmeyer, O. Soehnlein, L. Fraemohs, A. Zernecke, N. Schwarz, K. Reiss, A. Sarabi, L. Lindbom, T. M. Hackeng, et al. Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases Blood, May 7, 2009; 113(19): 4799 - 4809. [Abstract] [Full Text] [PDF]

				Q. Li, F. Jimenez-Krassel, J. J Ireland, and G. W Smith Gene expression profiling of bovine preovulatory follicles: gonadotropin surge and prostanoid-dependent up-regulation of genes potentially linked to the ovulatory process Reproduction, February 1, 2009; 137(2): 297 - 307. [Abstract] [Full Text] [PDF]

				J. L. Klessner, B. V. Desai, E. V. Amargo, S. Getsios, and K. J. Green EGFR and ADAMs Cooperate to Regulate Shedding and Endocytic Trafficking of the Desmosomal Cadherin Desmoglein 2 Mol. Biol. Cell, January 1, 2009; 20(1): 328 - 337. [Abstract] [Full Text] [PDF]

				A. Szklarczyk, O. Ewaleifoh, J.-C. Beique, Y. Wang, D. Knorr, N. Haughey, T. Malpica, M. P. Mattson, R. Huganir, and K. Conant MMP-7 cleaves the NR1 NMDA receptor subunit and modifies NMDA receptor function FASEB J, November 1, 2008; 22(11): 3757 - 3767. [Abstract] [Full Text] [PDF]

				B. Ponnuchamy and R. A. Khalil Role of ADAMs in Endothelial Cell Permeability: Cadherin Shedding and Leukocyte Rolling Circ. Res., May 23, 2008; 102(10): 1139 - 1142. [Full Text] [PDF]