Fluid mechanical factors are thought to influence vascular morphogenesis. Here we show how blood shear stress regulates the shape of a thrombus-neointima-like tissue on a polymer micro-cylinder implanted in the center of the rat vena cava with the micro-cylinder perpendicular to blood flow. In this model, the micro-cylinder is exposed to a laminar flow with a known shear stress field in the leading region and a vortex flow in the trailing region. At 1, 5, 10, 20, and 30 days after implantation, it was found that the micro-cylinder was encapsulated by a thrombus-neointima-like tissue with a streamlined body profile. The highest growth rate of the thrombus-neointima-like tissue was found along the trailing and leading stagnation edges of the micro-cylinder. Blood shear stress in the laminar flow region was inversely correlated with the rate of thrombus formation and cell proliferation, and the percentage of smooth muscle α actin-positive cells. These biological changes were also found in the trailing vortex flow region, which was associated with lowered shear stress. These results suggest that blood shear stress regulates the rate of thrombus and neointimal formation and, thus, influences the shape of the thrombus-neointima-like structure in the present model.

1.
Asakura
,
T.
, and
Karino
,
T.
,
1990
, “
Flow Patterns and Spacial Distribution of Atherosclerotic Lesions in Human Coronary Arteries
,”
Circ. Res.
,
66
, pp.
1045
1066
.
2.
Caro
,
C. G.
,
Fitz-Gerald
,
J. M.
, and
Schroter
,
R. C.
,
1969
, “
Arterial Wall Shear Stress and Distribution of Early Atheroma in Man
,”
Nature (London)
,
223
, pp.
1159
1161
.
3.
Gibson
,
C. M.
,
Diaz
,
L.
,
Kandarpa
,
K.
,
Sacks
,
F. M.
,
Pasternak
,
R. C.
,
Sandor
,
T.
,
Feldman
,
C.
, and
Stone
,
P. H.
,
1993
, “
Relation of Vessel Wall Shear Stress to Atherosclerosis Progression in Human Coronary Arteries
,”
Arterioscler. Thromb.
,
13
, pp.
310
315
.
4.
Gnasso
,
A.
,
Carallo
,
C.
,
Irace
,
C.
,
Spagnuolo
,
V.
,
De Novara
,
G.
,
Mattioli
,
P. L.
, and
Pujia
,
A.
,
1996
, “
Association Between Intima-Media Thickness and Wall Shear Stress in Common Carotid Arteries in Healthy Male Subjects
,”
Circulation
,
94
, pp.
3257
3262
.
5.
Kolpakov
,
V.
,
Polishchuk
,
R.
,
Bannykh
,
S.
,
Rekhter
,
M.
,
Solovjev
,
P.
,
RoManov
,
Y.
,
Tararak
,
E.
,
Antonov
,
A.
, and
Mironov
,
A.
,
1996
, “
Atherosclerosis-Prone Branch Regions in Human Aorta: Microarchitecture and Cell Composition of Intima
,”
Atherosclerosis (Berlin)
122
, pp.
173
189
.
6.
Ku
,
D. N.
,
Giddens
,
D. P.
,
Zarins
,
C. K.
, and
Glagov
,
S.
,
1985
, “
Pulsatile flow and Atherosclerosis in the Human Carotid Bifurcation. Positive Correlation Between Plaque Location and Low Oscillating Shear Stress
,”
Arteriosclerosis (Dallas)
5
, pp.
293
302
.
7.
Liu
,
S. Q.
,
1998
, “
Prevention of Focal Intimal Hyperplasia in Rat Vein Grafts by Using a Tissue Engineering Approach
,”
Atherosclerosis (Berlin)
140
, pp.
365
377
.
8.
Zarins
,
C. K.
,
Giddens
,
D. P.
,
Bharadvaj
,
B. K.
,
Sottiurai
,
V. S.
,
Mabon
,
R. F.
, and
Glagov
,
S.
,
1983
, “
Carotid Bifurcation Atherosclerosis. Quantitative Correlation of Plaque Localization With Flow Velocity Profiles and Wall Shear Stress
,”
Circ. Res.
,
53
, pp.
502
514
.
9.
Geary
,
R. L.
,
Kohler
,
T. R.
,
Vergel
,
S.
,
KirkMan
,
T. R.
, and
Clowes
,
A. W.
,
1994
, “
Time Course of Flow-Induced Smooth Muscle Cell Proliferation and Intimal Thickening in Endothelialized Baboon Vascular Grafts
,”
Circ. Res.
,
74
, pp.
14
23
.
10.
Kraiss
,
L. W.
,
Geary
,
R. L.
,
Mattsson
,
E. J. R.
,
Vergel
,
S.
,
Au
,
T. Y. P.
, and
Clowes
,
A. W.
,
1996
, “
Acute Reduction in Blood Flow and Shear Stress Induce Platelet-Derived Growth Factor-A Expression in Baboon Prosthetic Grafts
,”
Circ. Res.
,
79
, pp.
45
53
.
11.
Liu
,
S. Q.
,
1999
, “
Focal Activation of Angiotensin II Type 1 Receptor and Smooth Muscle Cell Proliferation in the Neointima of Experimental Vein Grafts: Relation to Eddy Blood Flow
,”
Arterioscler., Thromb., Vasc. Biol.
,
19
, pp.
2630
2639
.
12.
Mondy
,
J. S.
,
Lindner
,
V.
,
Miyashiro
,
J. K.
,
Berk
,
B. C.
,
Dean
,
R. H.
, and
Geary
,
R. L.
,
1997
, “
Platelet-Derived Growth Factor Ligand and Receptor Expression in Response to Altered Blood Flow in Vivo
,”
Circ. Res.
,
81
, pp.
320
327
.
13.
Zand
,
T.
,
HoffMan
,
A. H.
,
Savilonis
,
B. J.
,
Underwood
,
J. M.
,
Nunnari
,
J. J.
,
Majno
,
G.
, and
Joris
,
I.
,
1999
, “
Lipid Dposition in Rat Aorta With Intraluminal Hemispherical Plug Stenosis. A morphological and Biophysical Study
,”
Am. J. Pathol.
,
155
, pp.
85
92
.
14.
LaBarbera
,
M.
,
1990
, “
Principles of Design of Fluid Transport Systems in Zoology
,”
Science
,
249
, pp.
992
1000
.
15.
Liu
,
S. Q.
,
2000
, “
Regulation of Neointimal Morphogenesis by Blood Shear Stress
,”
Adv. Bioeng.
,
48
, pp.
61
62
.
16.
Liu
,
S. Q.
, and
GoldMan
,
J.
,
2001
, “
Role of Blood Shear Stress in the Regulation of Vascular Smooth Muscle Cell Migration
,”
IEEE Trans. Biomed. Eng.
,
48
, pp.
474
483
.
17.
Schlichting, H., 1968, Boundary-Layer Theory, McGraw-Hill, N.Y., pp. 149–186.
18.
Cho
,
A.
,
Mitchell
,
L.
,
KoopMans
,
D.
, and
Langille
,
B. L.
,
1997
, “
Effects of Changes in Blood Flow Rate on Cell Death and Cell Proliferation in Carotid Arteries of Immature Rabbits
,”
Circ. Res.
,
81
, pp.
328
337
.
19.
Salzar
,
R. S.
,
Thubrikar
,
M. J.
, and
Eppink
,
R. T.
,
1995
, “
Pressure-Induced Mechanical Stress in the Carotid Artery Bifurcation: A Possible Correlation to Atherosclerosis
,”
J. Biomech.
,
28
, pp.
1333
40
.
20.
Chien
,
S.
,
Li
,
S.
, and
Shyy
,
Y. J.
,
1998
, “
Effects of Mechanical Forces on Signal Transduction and Gene Expression in Endothelial Cells
,”
Hypertension
,
31
, pp.
162
169
.
21.
Davies
,
P. F.
, and
Tripathi
,
S. C.
,
1993
, “
Mechanical Stress Mechanisms and the Cell. An Endothelial Paradigm
,”
Circ. Res.
,
72
, pp.
239
245
.
22.
Gimbrone
, Jr.,
M. A.
,
1999
, “
Vascular Endothelium, Hemodynamic Forces, and Atherogenesis
,”
Am. J. Pathol.
,
155
, pp.
1
5
.
23.
Langille
,
B. L.
,
1996
, “
Arterial Remodeling: Relation to Hemodynamics
,”
Can. J. Physiol. Pharmacol.
,
74
, pp.
834
841
.
24.
Mcintire
,
L. V.
,
Wagner
,
J. E.
,
Papadaki
,
M.
,
Whitson
,
P. A.
, and
Eskin
,
S. G.
,
1998
, “
Effect of Flow on Gene Regulation in Smooth Muscle Cells and Macromolecular Transport Across Endothelial Cell Monolayers
,”
Biol. Bull.
,
194
, pp.
394
399
.
25.
Nerem
,
R. M.
,
Alexander
,
R. W.
,
Chappell
,
D. C.
,
Medford
,
R. M.
,
Varner
,
S. E.
, and
Taylor
,
W. R.
,
1998
, “
The Study of the Influence of Flow on Vascular Endothelial Biology
,”
Am. J. Med. Sci.
,
316
, pp.
169
175
.
26.
Traub
,
O.
, and
Berk
,
B. C.
,
1998
, “
Laminar Shear Stress: Mechanism1s by which Endothelial Cells Transduce an Atheroprotective Force
,”
Arterioscler., Thromb., Vasc. Biol.
,
18
, pp.
677
685
.
27.
Liu
,
S. Q.
,
1999
, “
Biomechanical Basis of Vascular Tissue Engineering
,”
Crit. Rev. Biomed. Eng.
,
27
, pp.
75
148
.
28.
Azuma
,
N.
,
Akasaka
,
N.
,
Kito
,
H.
,
Ikeda
,
M.
,
Gahtan
,
V.
,
Sasajima
,
T.
, and
Sumpio
,
B. E.
,
2001
, “
Role of p38 MAP Kinase in Endothelial Cell Alignment Induced by Fluid Shear Stress
,”
Am. J. Physiol.
,
280
, pp.
189
197
.
29.
Li
,
Y-S.
,
Shyy
,
J. Y.
,
Li
,
S.
,
Lee
,
J. D.
,
Su
,
B.
,
Karin
,
M.
, and
Chien
,
S.
,
1996
, “
The Ras/JNK Pathway is Involved in the Shear-Induced Gene Expression
,”
Mol. Cell. Biol.
,
16
, pp.
5947
5954
.
30.
Tseng
,
H.
,
Peterson
,
T. E.
, and
Berk
,
B. C.
,
1995
, “
Fluid Shear Stress Stimulates Mitogenactivated Protein Kinase in Endothelial Cells
,”
Circ. Res.
,
77
, pp.
869
878
.
31.
Gudi
,
S. R.
,
Clark
,
C. B.
, and
Frangos
,
J. A.
,
1996
, “
Fluid Flow Rapidly Activates G Proteins in Human Endothelial Cells. Involvement of G Proteins in Mechanochemical Signal Transduction
,”
Circ. Res.
,
79
, pp.
834
839
.
32.
Gudi, S., Nolan, J. P., and Frangos, J. A., 1998, “Modulation of GTPase Activity of G Proteins by Fluid Shear Stress and Phospholipid Composition,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, pp. 2515–2519.
33.
Malek
,
A. M.
,
Gibbons
,
G. H.
,
Dzau
,
Y. J.
, and
Izumo
,
S.
,
1993
, “
Fluid Shear Stress Differentially Modulates Expression of Genes Encoding Basic Fibroblast Growth Factor and Platelet-Derived Growth Factor B Chain in Vascular Endothelium
,”
J. Clin. Invest.
,
92
, pp.
2013
2021
.
34.
Resnick
,
N.
,
Collins
,
T.
,
Atkinson
,
W.
,
Bonthron
,
D. T.
,
Dewey
, Jr.,
C. F.
, and
Gimbrone
,
M.
Jr.
,
1993
, “
Platelet-Derived Growth Factor B Chain Promotor Contains a Cis-acting Fluid Shear-Stress Responsive Element
,”
Proc. Natl. Acad. Sci. USA
, Vol.
90
, pp.
4591
4595
.
35.
Papadaki
,
M.
,
Ruef
,
J.
,
Nguyen
,
K. T.
,
Li
,
F.
,
Patterson
,
C.
,
Eskin
,
S. G.
,
McIntire
,
L. V.
, and
Runge
,
M. S.
,
1998
, “
Differential Regulation of Protease Activated Receptor-1 and Tissue Plasminogen Activator Expression by Shear Stress in Vascular Smooth Muscle Cells
,”
Circ. Res.
,
83
, pp.
1027
1034
.
36.
Moazzam
,
F.
,
DeLano
,
F. A.
,
Zweifach
,
B. W.
, and
Schmid-Schoenbein
,
G. W.
,
1997
, “
The Leukocyte Response to Fluid Stress
,”
Proc. Natl. Acad. Sci. USA
, Vol.
94
, pp.
5338
5343
.
37.
Girard
,
P. R.
, and
Nerem
,
R. M.
,
1995
, “
Shear Stress Modulates Endothelial Cell Morphology and F-Actin Organization Through the Regulation of Focal Adhesion-Associated Proteins
,”
J. Cell Physiol.
,
163
, pp.
179
193
.
38.
Langille
,
B. L.
,
Graham
,
J. J. K.
,
Kim
,
D.
, and
Gotlieb
,
A. I.
,
1991
, “
Dynamics of Shear-Induced Redistribution of F-actin in Endothelial Cells in Vivo
,”
Arterioscler. Thromb.
,
11
, pp.
1814
1820
.
39.
Barbee
,
K. A.
,
Davies
,
P. F.
, and
Lal
,
R.
,
1994
, “
Shear Stress-Induced Reorganization of the Surface Topography of Living Endothelial Cells Imaged by Atomic Force Microscopy
,”
Circ. Res.
,
74
, pp.
163
171
.
40.
Thoumine
,
O.
,
Ziegler
,
T.
,
Girard
,
P. R.
, and
Nerem
,
R. M.
,
1995
, “
Elongation of Confluent Endothelial Cells in Culture: the Importance of Fields of Force in the Associated Alterations of Their Cytoskeletal Structure
,”
Exp. Cell Res.
,
219
, pp.
427
441
.
41.
Liu
,
S. Q.
,
Yen
,
M.
, and
Fung
,
Y. C.
,
1994
, “
On Measuring the Third Dimension of Cultured Endothelial Cells
,”
Proc. Natl. Acad. Sci. USA
, Vol.
91
, pp.
8782
8786
.
You do not currently have access to this content.