Macrophage accumulation is one of the earliest events in atherosclerosis. Macrophages are derived from blood-borne monocytes that adhere to endothelium and transmigrate across the endothelium. In flowing blood monocytes are transported along streamlines, Contact is more likely at regions where curvature brings streamlines close to the vessel wall and flow reversal first occurs. In order for cells to adhere and activate signaling pathways that promote transmigration, the adhesive force arising from bond formation must resist the hydrodynamic force causing cells to detach. Firm adhesion in regions of flow reversal must still occur rapidly in order to resist higher shears tresses arising during systole. Recently we observed that adhesion of monocytic cells is enhanced by forces acting normal to the surface between the monocyte and endothelium. Bond formation increased leading to more stable adhesion. Normal forces arising from secondary flows may thus play an important role in creating adhesive forces able to resist detachment of monocytes from endothelium in the relatively high shear stress environment found in the arteries. These normal forces may be further enhanced by red cell interactions with monocytes about to contact or adhering to endothelium. Cell rolling and arrest involves bond and tether formation. The objective of the proposed research is to test the hypothesis that normal forces arising in regions of flow recirculation enhance monocyte adhesion by compression of the microvitli and increased bond formation between monocytes and endothelium. A combination of micropipette aspiration experiments, flow chamber adhesion measurements and total internal reflection fluorescence microscopy (TIRF) will be used to test this hypothesis in vitro through the following specific aims: (1) characterize the viscoelastic behavior of monocytic cells, endothelium and tether formation (2) Investigate the effect of normal forces on the biophysics of bond and tether formation; (3) characterize the receptors involved in adhesion mediated by normal forces;(4) Determine the effect of normal; and shear forces on the contact area of rnonocytes; and (5) Examine the role of normal forces in enhanced monocyte adhesion near flow reattachment. Experimental studies will be aided by application of theoretical studies to model the adhesion of monocytes to endothelium. Results from this research will provide new information about the mechanism by which monocytes adhere to arterial endothelium in atherosclerosis-prone regions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL057446-04A1
Application #
6682524
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2003-07-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$231,000
Indirect Cost
Name
Duke University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Khismatullin, Damir B; Truskey, George A (2012) Leukocyte rolling on P-selectin: a three-dimensional numerical study of the effect of cytoplasmic viscosity. Biophys J 102:1757-66
Wallace, Charles S; Truskey, George A (2010) Direct-contact co-culture between smooth muscle and endothelial cells inhibits TNF-alpha-mediated endothelial cell activation. Am J Physiol Heart Circ Physiol 299:H338-46
Grailer, Jamison J; Kodera, Masanari; Steeber, Douglas A (2009) L-selectin: role in regulating homeostasis and cutaneous inflammation. J Dermatol Sci 56:141-7
McKinney, V Z; Rinker, K D; Truskey, G A (2006) Normal and shear stresses influence the spatial distribution of intracellular adhesion molecule-1 expression in human umbilical vein endothelial cells exposed to sudden expansion flow. J Biomech 39:806-17
Rinker, Kristina D; Kirkpatrick, Allison P; Ting-Beall, H Ping et al. (2004) Linoleic acid increases monocyte deformation and adhesion to endothelium. Atherosclerosis 177:275-85
Khismatullin, Damir B; Truskey, George A (2004) A 3D numerical study of the effect of channel height on leukocyte deformation and adhesion in parallel-plate flow chambers. Microvasc Res 68:188-202
Longest, P Worth; Kleinstreuer, Clement; Truskey, George A et al. (2003) Relation between near-wall residence times of monocytes and early lesion growth in the rabbit aorto-celiac junction. Ann Biomed Eng 31:53-64
Truskey, George A; Barber, Kevin M; Rinker, Kristina D (2002) Factors influencing the nonuniform localization of monocytes in the arterial wall. Biorheology 39:325-9
Rinker, K D; Prabhakar, V; Truskey, G A (2001) Effect of contact time and force on monocyte adhesion to vascular endothelium. Biophys J 80:1722-32
Kleinstreuer, C; Hyun, S; Buchanan Jr, J R et al. (2001) Hemodynamic parameters and early intimal thickening in branching blood vessels. Crit Rev Biomed Eng 29:1-64

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