Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin-mediated cell-cell contacts.
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.
Orlova
Valeria V
VV
Experimental Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Economopoulou
Matina
M
Lupu
Florea
F
Santoso
Sentot
S
Chavakis
Triantafyllos
T
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D015820:Cadherins / Q000378:metabolism / Q000502:physiology*; D002199:Capillary Permeability / Q000235:genetics / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002450:Cell Communication / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D004330:Drosophila / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D062726:Junctional Adhesion Molecules; D051379:Mice; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology; D012171:Retinal Vessels / Q000166:cytology / Q000502:physiology; D012869:Skin Absorption / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D015815:Cell Adhesion Molecules; D062726:Junctional Adhesion Molecules; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5