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Prior to establishing tight contact with the endothelium, cells such as leukocytes or cancer cells use the recognition between sialyl-Lewis^X ligands and E-selectin receptors to establish weak, reversible adhesion and to roll along the vessel wall. We study the physical aspects of this process by constructing a mimetic system that consists of a giant fluid vesicle with incorporated lipid-anchored sialyl-Lewis^X molecules that bind to E-selectin that is immobilized on the flat substrate. The vesicles also carry a certain fraction of repelling PEG2000 molecules. We analyze the equilibrium state of adhesion in detail by means of reflection interference contrast microscopy and find that the adhesion process relies purely on the formation of one or more adhesion domains within the vesicle−substrate contact zone. We find that the content of ligands in the vesicle must be above 5 mol % to establish specific contacts. All …