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Relationship between Molecular and Cellular Dissociation Rates for VLA-4/VCAM-1 Interaction in the Absence of Shear Stress

Gordon Zwartz ^*, Alexandre Chigaev ^*, Terry Foutz ^*, Richard S. Larson ^*, Richard Posner  and Larry A. Sklar ^*

^* Department of Pathology and Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico; and Department of Chemistry, Northern Arizona University, Flagstaff, Arizona

Correspondence: Address reprint requests to Prof. Larry A. Sklar, Department of Pathology and Cancer Center, University of New Mexico HSC, Albuquerque, NM 87131. Tel.: 505-272-4249; Fax: 505-272-6995; E-mail address: lsklar{at}salud.unm.edu.

The rate of leukocyte recruitment to and detachment from the vasculature contributes to cellular tethering, rolling, firm adherence, and migration across an endothelium layer. The molecular rates depend on the type and number of bound integrin or selectin adhesion molecules, shear force acting on the bound adhesion molecules, and affinity state of integrins. Although little is known of the effect that the number of adhesion molecules has on leukocyte recruitment, it has been shown that firm adhesion for cells in suspension may be mediated by small numbers of bound adhesion molecules. We studied the disaggregation of aggregates composed of B78H1 cells transfected with human vascular cell adhesion molecule-1 (VCAM-1) and human monoblastoid U937 cells expressing Very Late Antigen-4 (VLA-4). Aggregate disaggregation rates were obtained and compared to dissociation rates for soluble rhVCAM-1 ligand and monoblastoid U937 cells. Under conditions without shear stress, it was found that average cellular disaggregation rates were a factor of 1.3 ± 0.4 times slower than molecular dissociation rates for the 1 mM Mn²⁺ and 1 mM Mn²⁺ + 1 mM Ca²⁺ conditions. A simple mathematical model was used to predict how much smaller the dissociation constant would be if the number of bonds holding an aggregate varied from one bond to N bonds under conditions without shear stress. The average number of adhesion bonds holding the cell aggregates together was found to be 1.5 ± 0.7. This suggests that a few bonds were needed to form cellular aggregates and that increased aggregation was related to integrin affinity changes and not due to clustering or increased bond numbers.

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