Endothelial cells are known to respond to hemodynamic forces. Their phenotype has been suggested to differ between atheroprone and atheroprotective regions of the vasculature, which are characterized by the local hemodynamic environment. Once an atherosclerotic plaque has formed in a vessel, the obstruction creates complex spatial gradients in wall shear stress. Endothelial cell response to wall shear stress may be linked to the stability of coronary plaques. Unfortunately, in vitro studies of the endothelial cell involvement in plaque stability have been limited by unrealistic and simplified geometries, which cannot reproduce accurately the hemodynamics created by a coronary stenosis. Hence, in an attempt to better replicate the spatial wall shear stress gradient patterns in an atherosclerotic region, a three dimensional asymmetric stenosis model was created. Human abdominal aortic endothelial cells were exposed to steady flow (Re=50, 100, and 200 and τ=4.5dyn/cm2, 9dyn/cm2, and 18dyn/cm2) in idealized 50% asymmetric stenosis and straight/tubular in vitro models. Local morphological changes that occur due to magnitude, duration, and spatial gradients were quantified to identify differences in cell response. In the one dimensional flow regions, where flow is fully developed and uniform wall shear stress is observed, cells aligned in flow direction and had a spindlelike shape when compared with static controls. Morphological changes were progressive and a function of time and magnitude in these regions. Cells were more randomly oriented and had a more cobblestone shape in regions of spatial wall shear stress gradients. These regions were present, both proximal and distal, at the stenosis and on the wall opposite to the stenosis. The response of endothelial cells to spatial wall shear stress gradients both in regions of acceleration and deceleration and without flow recirculation has not been previously reported. This study shows the dependence of endothelial cell morphology on spatial wall shear stress gradients and demonstrates that care must be taken to account for altered phenotype due to geometric features. These results may help explain plaque stability, as cells in shoulder regions near an atherosclerotic plaque had a cobblestone morphology indicating that they may be more permeable to subendothelial transport and express prothrombotic factors, which would increase the risk of atherothrombosis.

1.
Rosamond
,
W.
,
Flegal
,
K.
,
Friday
,
G.
,
Furie
,
K.
,
Go
,
A.
,
Greenlund
,
K.
,
Haase
,
N.
,
Ho
,
M.
,
Howard
,
V.
,
Kissela
,
B.
,
Kittner
,
S.
,
Lloyd-Jones
,
D.
,
McDermott
,
M.
,
Meigs
,
J.
,
Moy
,
C.
,
Nichol
,
G.
,
O’Donnell
,
C. J.
,
Roger
,
V.
,
Rumsfeld
,
J.
,
Sorlie
,
P.
,
Steinberger
,
J.
,
Thom
,
T.
,
Wasserthiel-Smoller
,
S.
, and
Hong
,
Y.
, 2007, “
Heart Disease and Stroke Statistics—2007 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee
,”
Circulation
0009-7322,
115
(
5
), pp.
e69
e171
.
2.
DeBakey
,
M. E.
,
Lawrie
,
G. M.
, and
Glaeser
,
D. H.
, 1985, “
Patterns of Atherosclerosis and Their Surgical Significance
,”
Ann. Surg.
0003-4932,
201
(
2
), pp.
115
131
.
3.
Asakura
,
T.
, and
Karino
,
T.
, 1990, “
Flow Patterns and Spatial Distribution of Atherosclerotic Lesions in Human Coronary Arteries
,”
Circ. Res.
0009-7330,
66
(
4
), pp.
1045
1066
.
4.
Frangos
,
S. G.
,
Gahtan
,
V.
, and
Sumpio
,
B.
, 1999, “
Localization of Atherosclerosis: Role of Hemodynamics
,”
Arch. Surg.
,
134
(
10
), pp.
1142
1149
.
5.
Young
,
D. F.
, and
Tsai
,
F. Y.
, 1973, “
Flow Characteristics in Models of Arterial Stenoses. I. Steady Flow
,”
J. Biomech.
0021-9290,
6
(
4
), pp.
395
410
.
6.
Malek
,
A. M.
,
Alper
,
S. L.
, and
Izumo
,
S.
, 1999, “
Hemodynamic Shear Stress and Its Role in Atherosclerosis
,”
JAMA, J. Am. Med. Assoc.
0098-7484,
282
(
21
), pp.
2035
2042
.
7.
Gimbrone
,
M. A.
, Jr.
,
Topper
,
J. N.
,
Nagel
,
T.
,
Anderson
,
K. R.
, and
Garcia-Cardena
,
G.
, 2000, “
Endothelial Dysfunction, Hemodynamic Forces, and Atherogenesis
,”
Ann. N.Y. Acad. Sci.
0077-8923,
902
, pp.
230
239
.
8.
Depaola
,
N.
,
Gimbrone
,
M. A.
, Jr.
,
Davies
,
P. F.
, and
Dewey
,
C. F.
, Jr.
, 1992, “
Vascular Endothelium Responds to Fluid Shear Stress Gradients
,”
Arterioscler. Thromb.
1049-8834,
12
(
11
), pp.
1254
1257
.
9.
Blackman
,
B. R.
,
Barbee
,
K. A.
, and
Thibault
,
L. E.
, 2000, “
In Vitro Cell Shearing Device to Investigate the Dynamic Response of Cells in a Controlled Hydrodynamic Environment
,”
Ann. Biomed. Eng.
0090-6964,
28
(
4
), pp.
363
372
.
10.
Garcia-Cardena
,
G.
,
Comander
,
J.
,
Anderson
,
K. R.
,
Blackman
,
B. R.
, and
Gimbrone
,
M. A.
, Jr.
, 2001, “
Biomechanical Activation of Vascular Endothelium as a Determinant of Its Functional Phenotype
,”
Proc. Natl. Acad. Sci. U.S.A.
0027-8424,
98
(
8
), pp.
4478
4485
.
11.
Blackman
,
B. R.
,
Garcia-Cardena
,
G.
, and
Gimbrone
,
M. A.
, Jr.
, 2002, “
A New In Vitro Model to Evaluate Differential Responses of Endothelial Cells to Simulated Arterial Shear Stress Waveforms
,”
ASME J. Biomech. Eng.
0148-0731,
124
(
4
), pp.
397
407
.
12.
Qiu
,
Y.
, and
Tarbell
,
J. M.
, 2000, “
Interaction Between Wall Shear Stress and Circumferential Strain Affects Endothelial Cell Biochemical Production
,”
J. Vasc. Res.
1018-1172,
37
(
3
), pp.
147
157
.
13.
Peng
,
X.
,
Recchia
,
F. A.
,
Byrne
,
B. J.
,
Wittstein
,
I. S.
,
Ziegelstein
,
R. C.
, and
Kass
,
D. A.
, 2000, “
In Vitro System to Study Realistic Pulsatile Flow and Stretch Signaling in Cultured Vascular Cells
,”
Am. J. Physiol.: Cell Physiol.
0363-6143,
279
(
3
), pp.
C797
C805
.
14.
Ziegler
,
T.
,
Bouzourene
,
K.
,
Harrison
,
V. J.
,
Brunner
,
H. R.
, and
Hayoz
,
D.
, 1998, “
Influence of Oscillatory and Unidirectional Flow Environments on the Expression of Endothelin and Nitric Oxide Synthase in Cultured Endothelial Cells
,”
Arterioscler., Thromb., Vasc. Biol.
1079-5642,
18
(
5
), pp.
686
692
.
15.
Farcas
,
M.
,
Rouleau
,
L.
,
Fraser
,
R.
, and
Leask
,
R.
, 2009, “
The Development of 3-D, In Vitro, Endothelial Culture Models for the Study of Coronary Artery Disease
,”
Biomed. Eng. Online
1475-925X,
8
(
30
), pp.
1
11
.
16.
Rouleau
,
L.
,
Rossi
,
J.
, and
Leask
,
R. L.
, 2010, “
The Response of Human Aortic Endothelial Cells in a Stenotic Hemodynamic Environment: Effect of Duration, Magnitude and Spatial Gradients in Wall Shear Stress
,”
J. Biomech. Eng.
0148-0731
132
(
7
), pp.
071015
.
17.
Zhang
,
J. N.
,
Bergeron
,
A. L.
,
Yu
,
Q.
,
Sun
,
C.
,
McIntire
,
L. V.
,
Lopez
,
J. A.
, and
Dong
,
J. F.
, 2002, “
Platelet Aggregation and Activation Under Complex Patterns of Shear Stress
,”
Thromb. Haemostasis
0340-6245,
88
(
5
), pp.
817
821
.
18.
Zhao
,
S.
,
Suciu
,
A.
,
Ziegler
,
T.
,
Moore
,
J. E.
, Jr.
,
Burki
,
E.
,
Meister
,
J. J.
, and
Brunner
,
H. R.
, 1995, “
Synergistic Effects of Fluid Shear Stress and Cyclic Circumferential Stretch on Vascular Endothelial Cell Morphology and Cytoskeleton
,”
Arterioscler., Thromb., Vasc. Biol.
1079-5642,
15
(
10
), pp.
1781
1786
.
19.
White
,
C. R.
,
Haidekker
,
M.
,
Bao
,
X.
, and
Frangos
,
J. A.
, 2001, “
Temporal Gradients in Shear, But Not Spatial Gradients, Stimulate Endothelial Cell Proliferation
,”
Circulation
0009-7322,
103
(
20
), pp.
2508
2513
.
20.
Haidekker
,
M. A.
,
White
,
C. R.
, and
Frangos
,
J. A.
, 2001, “
Analysis of Temporal Shear Stress Gradients During the Onset Phase of Flow Over a Backward-Facing Step
,”
ASME J. Biomech. Eng.
0148-0731,
123
(
5
), pp.
455
463
.
21.
White
,
C. R.
,
Stevens
,
H. Y.
,
Haidekker
,
M.
, and
Frangos
,
J. A.
, 2005, “
Temporal Gradients in Shear, But Not Spatial Gradients, Stimulate ERK1/2 Activation in Human Endothelial Cells
,”
Am. J. Physiol. Heart Circ. Physiol.
0363-6135,
289
(
6
), pp.
H2350
H2355
.
22.
Truskey
,
G. A.
,
Barber
,
K. M.
,
Robey
,
T. C.
,
Olivier
,
L. A.
, and
Combs
,
M. P.
, 1995, “
Characterization of a Sudden Expansion Flow Chamber to Study the Response of Endothelium to Flow Recirculation
,”
ASME J. Biomech. Eng.
0148-0731,
117
(
2
), pp.
203
210
.
23.
McKinney
,
V. Z.
,
Rinker
,
K. D.
, and
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.
0021-9290,
39
(
5
), pp.
806
817
.
24.
Nagel
,
T.
,
Resnick
,
N.
,
Dewey
,
C. F.
, Jr.
, and
Gimbrone
,
M. A.
, Jr.
, 1999, “
Vascular Endothelial Cells Respond to Spatial Gradients in Fluid Shear Stress by Enhanced Activation of Transcription Factors
,”
Arterioscler., Thromb., Vasc. Biol.
1079-5642,
19
(
8
), pp.
1825
1834
.
25.
Tardy
,
Y.
,
Resnick
,
N.
,
Nagel
,
T.
,
Gimbrone
,
M. A.
, Jr.
, and
Dewey
,
C. F.
, Jr.
, 1997, “
Shear Stress Gradients Remodel Endothelial Monolayers In Vitro via a Cell Proliferation-Migration-Loss Cycle
,”
Arterioscler., Thromb., Vasc. Biol.
1079-5642,
17
(
11
), pp.
3102
3106
.
26.
LaMack
,
J. A.
, and
Friedman
,
M. H.
, 2007, “
Individual and Combined Effects of Shear Stress Magnitude and Spatial Gradient on Endothelial Cell Gene Expression
,”
Am. J. Physiol. Heart Circ. Physiol.
0363-6135,
293
(
5
), pp.
H2853
H2859
.
27.
Brunette
,
J.
,
Mongrain
,
R.
,
Cloutier
,
G.
,
Bertrand
,
M.
,
Bertrand
,
O. F.
, and
Tardif
,
J. C.
, 2001, “
A Novel Realistic Three-Layer Phantom for Intravascular Ultrasound Imaging
,”
Int. J. Cardiovasc. Imaging
1569-5794,
17
(
5
), pp.
371
381
.
28.
Brunette
,
J.
,
Mongrain
,
R.
,
Laurier
,
J.
,
Galaz
,
R.
, and
Tardif
,
J. C.
, 2008, “
3D Flow Study in a Mildly Stenotic Coronary Artery Phantom Using a Whole Volume PIV Method
,”
Med. Eng. Phys.
1350-4533,
30
(
9
), pp.
1193
1200
.
29.
Couch
,
G. G.
,
Johnston
,
K. W.
, and
Ojha
,
M.
, 1996, “
Full-Field Flow Visualization and Velocity Measurement With a Photochromic Grid Method
,”
Meas. Sci. Technol.
0957-0233,
7
(
9
), pp.
1238
1246
.
30.
Ojha
,
M.
, 1994, “
Wall Shear Stress Temporal Gradient and Anastomotic Intimal Hyperplasia
,”
Circ. Res.
0009-7330,
74
(
6
), pp.
1227
1231
.
31.
Ojha
,
M.
,
Cobbold
,
R. S. C.
,
Johnston
,
K. W.
, and
Hummel
,
R. L.
, 1989, “
Pulsatile Flow Through Constricted Tubes: an Experimental Investigation Using Photochromic Tracer Methods
,”
J. Fluid Mech.
0022-1120,
203
(
1
), pp.
173
197
.
32.
Leask
,
R. L.
,
Wayne
,
J. K.
, and
Ojha
,
M.
, 2004, “
Hemodynamic Effects of Clot Entrapment in the TrapEase Inferior Vena Cava Filter
,”
J. Vasc. Interv. Radiol.
1051-0443,
15
(
5
), pp.
485
490
.
33.
Rouleau
,
L.
,
Rossi
,
J.
, and
Leask
,
R. L.
, 2010, “
Concentration and Time Effects of Dextran Exposure on Endothelial Cell Viability, Attachment, and Inflammatory Marker Expression In Vitro
,”
Ann. Biomed. Eng.
0090-6964
38
(
4
), pp
1451
1462
.
34.
Rouleau
,
L.
,
Farcas
,
M.
,
Tardif
,
J. C.
,
Thorin
,
E.
,
Mongrain
,
R.
, and
Leask
,
R. L.
, 2006, “
Endothelial Cell Morphology and Response to Shear Stress in an Asymmetric Stenosis Model
,”
J. Biomech.
0021-9290,
39
(
1
), p.
S312
.
35.
Rouleau
,
L.
,
Farcas
,
M.
,
Copland
,
I.
,
Tardif
,
J. C.
,
Mongrain
,
R.
, and
Leask
,
R. L.
, 2009, “
Morphological and Functional Flow-Induced Response of Endothelial Cells and Adhesive Properties of Leukocytes in 3D Stenotic Models
,”
IFMBE Proceedings of the 4th European Conference of the International Federation for Medical and Biological Engineering
, Vol.
22
,
Springer
,
Berlin Heidelberg
, pp.
2015
2018
.
36.
Nerem
,
R. M.
,
Levesque
,
M. J.
, and
Cornhill
,
J. F.
, 1981, “
Vascular Endothelial Morphology as an Indicator of the Pattern of Blood Flow
,”
ASME J. Biomech. Eng.
0148-0731,
103
(
3
), pp.
172
176
.
37.
Davies
,
P. F.
,
Barbee
,
K. A.
,
Volin
,
M. V.
,
Robotewskyj
,
A.
,
Chen
,
J.
,
Joseph
,
L.
,
Griem
,
M. L.
,
Wernick
,
M. N.
,
Jacobs
,
E.
,
Polacek
,
D. C.
,
Depaola
,
N.
, and
Barakat
,
A. I.
, 1997, “
Spatial Relationships in Early Signaling Events of Flow-Mediated Endothelial Mechanotransduction
,”
Annu. Rev. Physiol.
0066-4278,
59
, pp.
527
549
.
38.
Nagel
,
T.
,
Resnick
,
N.
,
Atkinson
,
W. J.
,
Dewey
,
C. F.
, Jr.
, and
Gimbrone
,
M. A.
, Jr.
, 1994, “
Shear Stress Selectively Upregulates Intercellular Adhesion Molecule-1 Expression in Cultured Human Vascular Endothelial Cells
,”
J. Clin. Invest.
0021-9738,
94
(
2
), pp.
885
891
.
39.
Gimbrone
,
M. A.
, Jr.
,
Resnick
,
N.
,
Nagel
,
T.
,
Khachigian
,
L. M.
,
Collins
,
T.
, and
Topper
,
J. N.
, 1997, “
Hemodynamics, Endothelial Gene Expression, and Atherogenesis
,”
Ann. N.Y. Acad. Sci.
0077-8923,
811
, pp.
1
11
.
40.
Cicha
,
I.
,
Goppelt-Struebe
,
M.
,
Yilmaz
,
A.
,
Daniel
,
W. G.
, and
Garlichs
,
C. D.
, 2008, “
Endothelial Dysfunction and Monocyte Recruitment in Cells Exposed to Non-Uniform Shear Stress
,”
Clin. Hemorheol Microcirc
1386-0291,
39
(
1–4
), pp.
113
119
.
41.
Cicha
,
I.
,
Beronov
,
K.
,
Ramirez
,
E. L.
,
Osterode
,
K.
,
Goppelt-Struebe
,
M.
,
Raaz
,
D.
,
Yilmaz
,
A.
,
Daniel
,
W. G.
, and
Garlichs
,
C. D.
, 2009, “
Shear Stress Preconditioning Modulates Endothelial Susceptibility to Circulating TNF-Alpha and Monocytic Cell Recruitment in a Simplified Model of Arterial Bifurcations
,”
Atherosclerosis
0021-9150,
207
(
1
), pp.
93
102
.
42.
Rossi
,
J.
,
Rouleau
,
L.
,
Tardif
,
J. C.
, and
Leask
,
R. L.
, 2009, “
Simvastatin Increases Endothelial Nitric Oxide Synthase Expression in Cultured Endothelial Cells Preconditioned With Steady Laminar Flow
,”
FASEB J.
0892-6638,
23
(
1
), p.
311
.
43.
Chiu
,
J. J.
,
Wang
,
D. L.
,
Chien
,
S.
,
Skalak
,
R.
, and
Usami
,
S.
, 1998, “
Effects of Disturbed Flow on Endothelial Cells
,”
ASME J. Biomech. Eng.
0148-0731,
120
(
1
), pp.
2
8
.
44.
Phelps
,
J. E.
, and
Depaola
,
N.
, 2000, “
Spatial Variations in Endothelial Barrier Function in Disturbed Flows In Vitro
,”
Am. J. Physiol. Heart Circ. Physiol.
0363-6135,
278
(
2
), pp.
H469
H476
.
45.
Dai
,
G.
,
Kaazempur-Mofrad
,
M. R.
,
Natarajan
,
S.
,
Zhang
,
Y.
,
Vaughn
,
S.
,
Blackman
,
B. R.
,
Kamm
,
R. D.
,
Garcia-Cardena
,
G.
, and
Gimbrone
,
M. A.
, Jr.
, 2004, “
Distinct Endothelial Phenotypes Evoked by Arterial Waveforms Derived From Atherosclerosis-Susceptible and -Resistant Regions of Human Vasculature
,”
Proc. Natl. Acad. Sci. U.S.A.
0027-8424,
101
(
41
), pp.
14871
14876
.
46.
Iiyama
,
K.
,
Hajra
,
L.
,
Iiyama
,
M.
,
Li
,
H.
,
DiChiara
,
M.
,
Medoff
,
B. D.
, and
Cybulsky
,
M. I.
, 1999, “
Patterns of Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 Expression in Rabbit and Mouse Atherosclerotic Lesions and at Sites Predisposed to Lesion Formation
,”
Circ. Res.
0009-7330,
85
(
2
), pp.
199
207
.
47.
Caro
,
C. G.
,
Fitz-Gerald
,
J. M.
, and
Schroter
,
R. C.
, 1971, “
Atheroma and Arterial Wall Shear: Observation, Correlation and Proposal of a Shear Dependent Mass Transfer Mechanism for Atherogenesis
,”
Proc. R. Soc., London, Ser. B
0950-1193,
177
, pp.
109
159
.
48.
Fry
,
D. L.
, 1968, “
Acute Vascular Endothelial Changes Associated With Increased Blood Velocity Gradients
,”
Circ. Res.
0009-7330,
22
, pp.
165
197
.
49.
Levesque
,
M. J.
, and
Nerem
,
R. M.
, 1985, “
The Elongation and Orientation of Cultured Endothelial Cells in Response to Shear Stress
,”
ASME J. Biomech. Eng.
0148-0731,
107
(
4
), pp.
341
347
.
50.
Levesque
,
M. J.
,
Liepsch
,
D.
,
Moravec
,
S.
, and
Nerem
,
R. M.
, 1986, “
Correlation of Endothelial Cell Shape and Wall Shear Stress in a Stenosed Dog Aorta
,”
Arteriosclerosis
0276-5047,
6
(
2
), pp.
220
229
.
51.
Helmlinger
,
G.
,
Geiger
,
R. V.
,
Schreck
,
S.
, and
Nerem
,
R. M.
, 1991, “
Effects of Pulsatile Flow on Cultured Vascular Endothelial Cell Morphology
,”
ASME J. Biomech. Eng.
0148-0731,
113
(
2
), pp.
123
131
.
52.
Nerem
,
R. M.
, 1993, “
Hemodynamics and the Vascular Endothelium
,”
ASME J. Biomech. Eng.
0148-0731,
115
(
4B
), pp.
510
514
.
53.
Helmlinger
,
G.
,
Berk
,
B. C.
, and
Nerem
,
R. M.
, 1995, “
Calcium Responses of Endothelial Cell Monolayers Subjected to Pulsatile and Steady Laminar Flow Differ
,”
Am. J. Physiol.
0002-9513,
38
, pp.
C367
C375
.
54.
Bao
,
X.
,
Lu
,
C.
, and
Frangos
,
J. A.
, 1999, “
Temporal Gradient in Shear But Not Steady Shear Stress Induces PDGF-A and MCP-1 Expression in Endothelial Cells: Role of NO, NF{Kappa}B, and Egr-1
,”
Arterioscler., Thromb., Vasc. Biol.
1079-5642,
19
(
4
), pp.
996
1003
.
55.
Eskin
,
S. G.
,
Ives
,
C. L.
,
McIntire
,
L. V.
, and
Navarro
,
L. T.
, 1984, “
Response of Cultured Endothelial Cells to Steady Flow
,”
Microvasc. Res.
0026-2862,
28
(
1
), pp.
87
94
.
56.
Davies
,
P. F.
,
Dewey
,
C. F.
, Jr.
,
Bussolari
,
S. R.
,
Gordon
,
E. J.
, and
Gimbrone
,
M. A.
, Jr.
, 1984, “
Influence of Hemodynamic Forces on Vascular Endothelial Function. In Vitro Studies of Shear Stress and Pinocytosis in Bovine Aortic Cells
,”
J. Clin. Invest.
0021-9738,
73
(
4
), pp.
1121
1129
.
57.
Davies
,
P. F.
,
Remuzzi
,
A.
,
Gordon
,
E. J.
,
Dewey
,
C. F.
, Jr.
, and
Gimbrone
,
M. A.
, Jr.
, 1986, “
Turbulent Fluid Shear Stress Induces Vascular Endothelial Cell Turnover in Vitro
,”
Proc. Natl. Acad. Sci. U.S.A.
0027-8424,
83
(
7
), pp.
2114
2117
.
58.
Dewey
,
C. F.
, Jr.
,
Bussolari
,
S. R.
,
Gimbrone
,
M. A.
, Jr.
, and
Davies
,
P. F.
, 1981, “
The Dynamic Response of Vascular Endothelial Cells to Fluid Shear Stress
,”
ASME J. Biomech. Eng.
0148-0731,
103
(
3
), pp.
177
185
.
59.
Topper
,
J. N.
,
Cai
,
J.
,
Falb
,
D.
, and
Gimbrone
,
M. A.
, Jr.
, 1996, “
Identification of Vascular Endothelial Genes Differentially Responsive to Fluid Mechanical Stimuli: Cyclooxygenase-2, Manganese Superoxide Dismutase, and Endothelial Cell Nitric Oxide Synthase Are Selectively Up-Regulated by Steady Laminar Shear Stress
,”
Proc. Natl. Acad. Sci. U.S.A.
0027-8424,
93
(
19
), pp.
10417
10422
.
60.
Levesque
,
M. J.
, and
Nerem
,
R. M.
, 1989, “
The Study of Rheological Effects on Vascular Endothelial Cells in Culture
,”
Biorheology
0006-355X,
26
(
2
), pp.
345
357
.
61.
Remuzzi
,
A.
,
Dewey
,
C. F.
, Jr.
,
Davies
,
P. F.
, and
Gimbrone
,
M. A.
, Jr.
, 1984, “
Orientation of Endothelial Cells in Shear Fields In Vitro
,”
Biorheology
0006-355X,
21
(
4
), pp.
617
630
.
62.
Resnick
,
N.
, and
Gimbrone
,
M. A.
, Jr.
, 1995, “
Hemodynamic Forces Are Complex Regulators of Endothelial Gene Expression
,”
FASEB J.
0892-6638,
9
(
10
), pp.
874
882
.
63.
Hajra
,
L.
,
Evans
,
A. I.
,
Chen
,
M.
,
Hyduk
,
S. J.
,
Collins
,
T.
, and
Cybulsky
,
M. I.
, 2000, “
The NF-Kappa B Signal Transduction Pathway in Aortic Endothelial Cells Is Primed for Activation in Regions Predisposed to Atherosclerotic Lesion Formation
,”
Proc. Natl. Acad. Sci. U.S.A.
0027-8424,
97
(
16
), pp.
9052
9057
.
64.
Walpola
,
P. L.
,
Gotlieb
,
A. I.
,
Cybulsky
,
M. I.
, and
Langille
,
B. L.
, 1995, “
Expression of ICAM-1 and VCAM-1 and Monocyte Adherence in Arteries Exposed to Altered Shear Stress
,”
Arterioscler., Thromb., Vasc. Biol.
1079-5642,
15
(
1
), pp.
2
10
.
65.
Boo
,
Y. C.
, and
Jo
,
H.
, 2003, “
Flow-Dependent Regulation of Endothelial Nitric Oxide Synthase: Role of Protein Kinases
,”
Am. J. Physiol.: Cell Physiol.
0363-6143,
285
(
3
), pp.
C499
C508
.
66.
Cheng
,
C.
,
van Haperen
,
R.
,
de Waard
,
M.
,
van Damme
,
L. C. A.
,
Tempel
,
D.
,
Hanemaaijer
,
L.
,
van Cappellen
,
G. W. A.
,
Bos
,
J.
,
Slager
,
C. J.
,
Duncker
,
D. J.
,
van der Steen
,
A. F. W.
,
de Crom
,
R.
, and
Krams
,
R.
, 2005, “
Shear Stress Affects the Intracellular Distribution of eNOS: Direct Demonstration by a Novel In Vivo Technique
,”
Blood
0006-4971,
106
(
12
), pp.
3691
3698
.
67.
Ganguli
,
A.
,
Persson
,
L.
,
Palmer
,
I. R.
,
Evans
,
I.
,
Yang
,
L.
,
Smallwood
,
R.
,
Black
,
R.
, and
Qwarnstrom
,
E. E.
, 2005, “
Distinct NF-κB Regulation by Shear Stress Through Ras-Dependent IκBα Oscillations: Real-Time Analysis of Flow-Mediated Activation in Live Cells
,”
Circ. Res.
0009-7330,
96
(
6
), pp.
626
634
.
68.
Morigi
,
M.
,
Zoja
,
C.
,
Figliuzzi
,
M.
,
Foppolo
,
M.
,
Micheletti
,
G.
,
Bontempelli
,
M.
,
Saronni
,
M.
,
Remuzzi
,
G.
, and
Remuzzi
,
A.
, 1995, “
Fluid Shear Stress Modulates Surface Expression of Adhesion Molecules by Endothelial Cells
,”
Blood
0006-4971,
85
(
7
), pp.
1696
1703
.
69.
Miao
,
H.
,
Hu
,
Y. L.
,
Shiu
,
Y. T.
,
Yuan
,
S.
,
Zhao
,
Y.
,
Kaunas
,
R.
,
Wang
,
Y.
,
Jin
,
G.
,
Usami
,
S.
, and
Chien
,
S.
, 2005, “
Effects of Flow Patterns on the Localization and Expression of VE-Cadherin at Vascular Endothelial Cell Junctions: In Vivo and In Vitro Investigations
,”
J. Vasc. Res.
1018-1172,
42
(
1
), pp.
77
89
.
70.
Navarro
,
P.
,
Ruco
,
L.
, and
Dejana
,
E.
, 1998, “
Differential Localization of VE- and N-Cadherins in Human Endothelial Cells: VE-Cadherin Competes With N-Cadherin for Junctional Localization
,”
J. Cell Biol.
0021-9525,
140
(
6
), pp.
1475
1484
.
71.
Schnittler
,
H. J.
,
Schneider
,
S. W.
,
Raifer
,
H.
,
Luo
,
F.
,
Dieterich
,
P.
,
Just
,
I.
, and
Aktories
,
K.
, 2001, “
Role of Actin Filaments in Endothelial Cell-Cell Adhesion and Membrane Stability Under Fluid Shear Stress
,”
Pflügers Arch.
,
442
(
5
), pp.
675
687
.
72.
Ukropec
,
J. A.
,
Hollinger
,
M. K.
, and
Woolkalis
,
M. J.
, 2002, “
Regulation of VE-Cadherin Linkage to the Cytoskeleton in Endothelial Cells Exposed to Fluid Shear Stress
,”
Exp. Cell Res.
0014-4827,
273
(
2
), pp.
240
247
.
73.
Rouleau
,
L.
,
Copland
,
I. B.
,
Tardif
,
J. C.
,
Mongrain
,
R.
, and
Leask
,
R. L.
, 2009, “
Neutrophil Adhesion on Endothelial Cells in a Novel Asymmetric Stenosis Model: Effect of Wall Shear Stress Gradients
,”
Ann. Biomed. Eng.
0090-6964, in press.
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