The Journal of Experimental Medicine
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Published online 20 November 2006 doi:10.1084/jem.20051730
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 12, 2703-2714
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ARTICLE

 Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin–mediated cell–cell contacts

Valeria V. Orlova1,3, Matina Economopoulou1, Florea Lupu2, Sentot Santoso4, and Triantafyllos Chavakis1

1 Experimental Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
2 Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104
3 Department of Medicine I, University Heidelberg, D-69120 Heidelberg, Germany
4 Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, D-35392 Giessen, Germany

CORRESPONDENCE Triantafyllos Chavakis: chavakist{at}mail.nih.gov

We recently reported that junctional adhesion molecule (JAM)-C plays a role in leukocyte transendothelial migration. Here, the role of JAM-C in vascular permeability was investigated in vitro and in vivo. As opposed to macrovascular endothelial cells that constitutively expressed JAM-C in cell–cell contacts, in quiescent microvascular endothelial cells, JAM-C localized mainly intracellularly, and was recruited to junctions upon short-term stimulation with vascular endothelial growth factor (VEGF) or histamine. Strikingly, disruption of JAM-C function decreased basal permeability and prevented the VEGF- and histamine-induced increases in human dermal microvascular endothelial cell permeability in vitro and skin permeability in mice. Permeability increases are essential in angiogenesis, and JAM-C blockade reduced hyperpermeability and neovascularization in hypoxia-induced retinal angiogenesis in mice. The underlying mechanisms of the JAM-C–mediated increase in endothelial permeability were studied. JAM-C was essential for the regulation of endothelial actomyosin, as revealed by decreased F-actin, reduced myosin light chain phosphorylation, and actin stress fiber formation due to JAM-C knockdown. Moreover, the loss of JAM-C expression resulted in stabilization of VE-cadherin–mediated interendothelial adhesion in a manner dependent on the small GTPase Rap1. Together, through modulation of endothelial contractility and VE-cadherin–mediated adhesion, JAM-C helps to regulate vascular permeability and pathologic angiogenesis.

Abbreviations used: cAMP, cyclic adenosine monophosphate; HDMEC, human dermal microvascular endothelial cell; HMVEC-L, human lung microvascular endothelial cell; HUVEC, human umbilical vein endothelial cell; HAEC, human aortic endothelial cell; JAM, junctional adhesion molecule; MLC, myosin light chain; PECAM, platelet endothelial cell adhesion molecule; PKA, protein kinase A; ROP, retinopathy of prematurity; smJAM, soluble mouse JAM; VEGF, vascular endothelial growth factor.


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