(262b) Factors Influencing Monocyte Transport to Arterial Endothelium

During the initial stages of atherosclerosis, the local accumulation of monocytes at in the arterial wall occurs following accumulation of low density lipoprotein. Once within the vessel wall monocytes transform into macrophages. The accumulation of monocytes is influenced by the presence of adhesion molecules on the endothelial cell surface and the local fluid dynamic environment. The complex flow field influences transport of monocytes to the endothelium and the local fluid forces affect endothelial cell adhesion. These hemodynamic factors, together with the state of activation of the endothelium, influence the localization of atherosclerosis. In normocholesterolemic rabbits intimal white blood cells are located in the arch, around the intercostals and around flow divider regions of the large abdominal branch arteries. Intimal monocyte/macrophages are spatially correlated with the distribution of sites of elevated low density lipoprotein permeability. Possible mechanisms for adhesion in the relatively high shear stress environment found in arteries include greater monocyte deformation and/or more frequent penetration of microvilli through steric and charge barriers. In vivo, secondary flows generate forces acting normal to the endothelial cell surface. These forces may cause compression of the microvilli or enable cells to overcome steric or electrostatic barriers, increasing adhesion. To investigate this, we examined monocyte adhesion to activated endothelium in shear and recirculating flow and performed computational simulations. To assess whether adhesion depended solely on bond kinetics, the shear rate was fixed and viscosity elevated with dextran to increase the shear stress (and hence the net force on the cell) independently of shear rate. At a fixed contact time in a uniform shear field, tethering frequencies increased, rolling velocities decreased, and median arrest durations increased with increasing shear stress. A kinetic analysis showed that, at a fixed contact time and increasing shear stress, bonds formed more frequently for rolling cells resulting in more short arrests, and more bonds formed for firmly arresting cells resulting in longer arrest duration. Linoleic concentrations below 23 µM decreased cortical tension and increased adhesion frequencies. Increased adhesion was not due to altered cell morphology or adhesion kinetics and occurred despite decreases in receptor expression (CD18 and CD11a). Decreasing cortical tension increased the probability that contact between MM6 cells and endothelium would produce an adhesive interaction, possibly due to increased deformation of the microvilli and the cell membrane cortex. However, more deformable cells rolled more erratically at low shear rates. The different behavior during initial contact and rolling suggest that adhesion is influenced by deformation of microvilli and a steric barrier. In recirculating flow, adhesion was characterized by short arrests in a narrow region on either side of the reattachment line. The median arrest time was longer than that observed at comparable shear stresses in a linear shear flow. The lifetimes of adhesion were analyzed using a model for multiple bond formation. For cells adhering near the reattachment line, the bond number per cell was greater than the value found for similar shear stresses under shear flow. Monocyte deposition patterns in vivo were simulated using transient three-dimensional blood flow computations. The deposition pattern traces a helical shape down the aorta with local elevation in monocyte adhesion around vessel branches. The cell deposition pattern was sensitive to the flow waveform. Monocyte deposition was correlated with the wall shear stress gradient and the wall shear stress angle gradient. The wall stress gradient and the normalized monocyte deposition fraction were correlated with the distribution of monocytes along the abdominal aorta and monocyte deposition is correlated with the measured distribution of monocytes around the major abdominal branches in the cholesterol-fed rabbit. These results suggest that the transport and deposition pattern of monocytes to arterial endothelium plays a significant role in the localization of lesions. More recently, three-dimensional models incorporating deformable cells with receptors on the ends of microvilli show that adhesion at physiological shear stresses requires cell deformation. These studies provide a more complete view of the manner by which monocytes adhere to lesion-prone regions of the arterial wall.