Monocyte-induced endothelial calcium signaling mediates early xenogeneic endothelial activation.
Hallmarks of delayed xenograft rejection include monocyte infiltration, endothelial cell activation and disruption of the endothelial barrier. The monocyte is an important initiator of this type of rejection because monocytes accumulate within hours after xenografting and prior monocyte depletion suppresses the development of this type of rejection. However, the mechanisms that mediate monocyte-induced xenograft injury are unclear at present. Here we report that human monocytes activate xenogeneic endothelial cells through calcium signals. Monocyte contact with porcine but not human endothelium leads to an endothelial calcium transient mediated via a G-protein-coupled receptor (GPCR) that results in up-regulation of porcine VCAM-1 and E-selectin. Although human monocyte adhesion was greater to porcine than to human endothelium, especially when studied under laminar flow, blockade of the xeno-specific endothelial calcium signals did not reduce adhesion of human monocytes to porcine endothelium. Human monocyte contact to porcine endothelium also resulted in reorganization of the F-actin cytoskeleton with a concomitant increase in endothelial monolayer permeability. In contrast to the effect on adhesion, these changes appear to be regulated through endothelial calcium signals. Taken together, these data suggest that human monocytes are capable of activating xenogeneic endothelial cells through calcium transients, as well as other distinct pathways.
Peterson
Mark D
MD
Division of Cardiac Surgery, The Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Vlasova
Ekaterina
E
Di Ciano-Oliveira
Caterina
C
Downey
Gregory P
GP
Cybulsky
Myron I
MI
Kapus
Andras
A
Waddell
Thomas K
TK
D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology*; D006084:Graft Rejection; D006801:Humans; D009000:Monocytes / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D013552:Swine; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D019040:E-Selectin; D043562:Receptors, G-Protein-Coupled; D019010:Vascular Cell Adhesion Molecule-1