ESAM supports neutrophil extravasation, activation of Rho, and VEGF-induced vascular permeability.
Endothelial cell-selective adhesion molecule (ESAM) is specifically expressed at endothelial tight junctions and on platelets. To test whether ESAM is involved in leukocyte extravasation, we have generated mice carrying a disrupted ESAM gene and analyzed them in three different inflammation models. We found that recruitment of lymphocytes into inflamed skin was unaffected by the gene disruption. However, the migration of neutrophils into chemically inflamed peritoneum was inhibited by 70% at 2 h after stimulation, recovering at later time points. Analyzing neutrophil extravasation directly by intravital microscopy in the cremaster muscle revealed that leukocyte extravasation was reduced (50%) in ESAM(-/-) mice without affecting leukocyte rolling and adhesion. Depletion of >98% of circulating platelets did not abolish the ESAM deficiency-related inhibitory effect on neutrophil extravasation, indicating that it is only ESAM at endothelial tight junctions that is relevant for the extravasation process. Knocking down ESAM expression in endothelial cells resulted in reduced levels of activated Rho, a GTPase implicated in the destabilization of tight junctions. Indeed, vascular permeability stimulated by vascular endothelial growth factor was reduced in ESAM(-/-) mice. Collectively, ESAM at endothelial tight junctions participates in the migration of neutrophils through the vessel wall, possibly by influencing endothelial cell contacts.
Wegmann
Frank
F
Max-Planck-Institute for Molecular Biomedicine and Institute of Cell Biology, University of Münster, D-48149 Münster, Germany.
Petri
Björn
B
Khandoga
Alexander Georg
AG
Moser
Christian
C
Khandoga
Andrej
A
Volkery
Stefan
S
Li
Hang
H
Nasdala
Ines
I
Brandau
Oliver
O
Fässler
Reinhard
R
Butz
Stefan
S
Krombach
Fritz
F
Vestweber
Dietmar
D
D000818:Animals; D002199:Capillary Permeability / Q000235:genetics / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D015815:Cell Adhesion Molecules; C428190:Esam protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D020741:rho GTP-Binding Proteins