| Atherosclerosis,
the leading cause of death in the developed world
and nearly the leading cause in the developing
world, is associated with systemic risk factors
including hypertension, smoking, hyperlipidemia,
and diabetes mellitus, among others. Nonetheless,
atherosclerosis remains a geometrically focal
disease, preferentially affecting the outer edges
of vessel bifurcations. In these predisposed
areas, hemodynamic shear stress, the frictional
force acting on the endothelial cell surface as a
result of blood flow, is weaker than in protected
regions. Studies have identified hemodynamic
shear stress as an important determinant of
endothelial function and phenotype. Arterial-level
shear stress (>15 dyne/cm2) induces
endothelial quiescence and an atheroprotective
gene expression profile, while low shear stress (<4
dyne/cm2), which is prevalent at
atherosclerosis-prone sites, stimulates an
atherogenic phenotype. The functional regulation
of the endothelium by local hemodynamic shear
stress provides a model for understanding the
focal propensity of atherosclerosis in the
setting of systemic factors and may help guide
future therapeutic strategies. JAMA.
1999;282:2035-2042
For
more than a century, hemodynamic forces have been
proposed as factors regulating blood vessel
structure1,
2
and influencing development of vascular pathology
such as atherosclerosis,3-5
aneurysms,6
poststenotic dilatations,7
and arteriovenous malformations.8
The flow of blood, by virtue of viscosity,
engenders on the luminal vessel wall and
endothelial surface a frictional force per unit
area known as hemodynamic shear stress.9-11
Shear stress has not only been shown to be a
critical determinant of vessel caliber,2,
11,
12
but has also been implicated in vascular
remodeling13,
14
and pathobiology.5
Atherosclerosis,
which remains the leading cause of death in the
developed world, is associated with genetic
predisposition and multiple risk factors such as
hypertension,15
smoking,16
hyperlipidemia,17
diabetes mellitus,18
social stress,19
sedentary lifestyle,18
viral infection,20
and possibly chlamydial infection.21
Despite the systemic nature of its associated
risk factors, atherosclerosis is a geometrically
focal disease that has a propensity to involve
the outer edges of blood vessel bifurcations.5,
22,
23
In these susceptible areas, blood flow is slow
and changes direction with the cardiac cycle,
resulting in a weak net hemodynamic shear stress.
In contrast, vessel regions that are exposed to
steady blood flow and a higher magnitude of shear
stress remain comparatively disease-free.4,
5,
22-25
Recent
animal, molecular, and cellular studies of the
endothelium's response to hemodynamic shear
stress have provided new insights into its
possible contribution to the pathogenesis of
atherosclerosis.10,
26-30
In this article, we review the recent advances
made in understanding the regulation of
endothelial cell function and gene expression by
shear stress. The modulation of endothelial
phenotype by local hemodynamic shear stress is
postulated to contribute to the focal geometric
progression of atherogenesis in the setting of
local and systemic risk factors that enhance the
thrombotic, proliferative, and inflammatory
components of this pathological process.
THE
VESSEL WALL AND HEMODYNAMIC FORCES
The
luminal surface of the blood vessel and its
endothelial surface are constantly exposed to
hemodynamic shear stress.9,
10
The magnitude of the shear stress can be
estimated in most of the vasculature by
Poiseuille's law9
(Figure
1,
A), which states that shear stress is
proportional to blood flow viscosity, and
inversely proportional to the third power of the
internal radius.11,
12,
31,
32
Measurements using different modalities show that
shear stress ranges from 1 to 6 dyne/cm2
in the venous system and between 10 and 70 dyne/cm2
in the arterial vascular network (Figure
1,
B). In numerous experiments, shear stress has
been shown to actively influence vessel wall
remodeling.1,
2,
33
Specifically, chronic increases in blood flow,
and consequently shear stress, such as seen in
the radial artery of dialysis patients proximal
to their arteriovenous fistula,34
or in feeder arteries supplying cerebral
arteriovenous malformations,8
lead to expansion of the luminal radius such that
mean shear stress is returned to its baseline
level.1,
34
Conversely, decreased shear stress resulting from
lower flow or blood viscosity35
induces a decrease in internal vessel radius.2
The net effect of these endothelial-mediated
compensatory responses is the maintenance of mean
arterial hemodynamic shear stress magnitude at
approximately 15 to 20 dyne/cm2.11,
34
This shear stress–stabilizing process is
dependent on intact endothelial function and is
abolished by prior selective destruction of the
endothelial monolayer.2
SHEAR
STRESS AND THE LOCALIZATION OF ATHEROSCLEROTIC
PLAQUES
Atherosclerotic
lesions long have been known to occur near
vascular branching points.36
Two contradictory hypotheses were advanced in the
1970s to explain this distribution of lesions.
The first implicated high shear stress (400 dyne/cm2)3
via direct endothelial injury and denudation, as
suggested by experimental exposure of endothelium
to supraphysiological shear stress (400 dyne/cm2).
The second, proposed by Caro et al,4
invoked low shear stress. Subsequent observations
and studies made in the last 3 decades have
validated the low-shear hypothesis of
atherosclerosis.5,
22,
24,
25
An explanatory mechanism for this association has
recently begun to evolve10,
26,
28-30
that can serve to explain the focal nature of the
inflammatory and proliferative responses to
injury that likely underlie atherogenesis.37
Atherogenesis
preferentially involves the outer walls of vessel
bifurcations and points of blood flow
recirculation and stasis (Figure
2,
A and B). In these geometrically predisposed
locations, fluid shear stress on the vessel wall
is significantly lower in magnitude and exhibits
directional changes and flow separation, features
absent from regions of the vascular tree
generally spared from atherosclerosis. Direct
measurements and fluid mechanical models of these
susceptible regions have revealed shear values on
the order of  4
dyne/cm2 compared with greater than 12
dyne/cm2 in the protected areas.5,
38
This association suggests that physiological or
elevated levels of shear stress might shield
against atherosclerosis via effects on the
endothelium, a hypothesis since confirmed in
cholesterol-fed miniature swine.39
Atherosclerotic
lesions co-localize with regions of low shear
stress throughout the arterial tree, from the
carotid artery bifurcation5,
23,
24
to the coronary,22,
40
infrarenal, and femoral artery vasculatures.41
High-speed cinematography and microparticle flow
analysis in postmortem coronary arterial trees
have correlated subintimal thickening with the
low wall shear stress of bifurcations22;
in contrast, pathologic lesions were absent from
the flow-dividers and inner wall where shear is
higher. The local rates of atherosclerosis
progression in patients with coronary artery
disease were found by serial quantitative
coronary angiography to correlate inversely with
shear stress magnitude, even when controlled for
systemic risk factors such as circulating levels
of lipoproteins.42
Flow
analysis and corresponding carotid endarterectomy
pathological sections showed greatest plaque
thickness in the outer wall of the carotid sinus
where flow shows stasis and shear is low in
magnitude and exhibits direction reversal13
(Figure
2).
Gnasso et al23
found that plaque-affected human carotid arteries
exhibited significantly lower wall shear stress
than did disease-free controls. The co-localization
of atherosclerosis to low-shear areas has also
been confirmed in the only location in the human
body where 2 arteries join to form a vascular
confluence, at the apex of the intracranial
vertebrobasilar junction.43
The
localization of atherosclerosis to low shear
regions has been further established in human
abdominal aortas both at autopsy41
and with noninvasive magnetic resonance phase
velocity mapping.44,
45
The same pattern of early plaque localization is
observed in young trauma patients,46
regardless of ethnic origin47
or dietary habits.48
En-face examination of endothelial surfaces in
human thoracic aortas reveals leukocyte adhesion,
accumulation of subendothelial macrophages and
lymphocytes, irregular endothelial morphology
with denuded regions covered with platelets, and
dilated intercellular clefts in the outer walls
but not in the inner walls or flow divider of
bifurcations.49
Measurements of wall shear stress using echo-Doppler
ultrasound in healthy young patients (aged 28-38
years) revealed a statistically significant
inverse relationship between intima-media
thickness in the carotid artery and local wall
shear stress.50
Similar localization of atherosclerotic lesions
has been reproduced in prospective experimental
animal studies in the aorta51,
52
and carotid arteries.53
These data together establish a clear correlation
between low wall shear stress and subintimal
thickening and atherosclerosis initiation. They
are consistent with the hypothesis that low wall
shear stress contributes importantly to
conditions that favor atherogenic transformation.
BIOLOGICAL
RESPONSE OF THE ENDOTHELIUM TO SHEAR STRESS
In
Vivo Responses to Surgically Induced Alterations
in Shear Stress
Additional insight into the importance of the
endothelial response to hemodynamics has also
been gained from animal experiments in which
shear stress has been acutely or chronically
altered. Increasing shear stress in the rat by
surgical construction of an aortocaval shunt
results in increased cyclic guanosine 3'5'-monophosphate
(presumably as a result of increased nitric oxide
release),54
and elevated shear increased endothelial nitric
oxide synthase (eNOS) messenger RNA (mRNA),
protein, and activity in high-shear stressed
aortas compared with sham-operated controls.55
These increases were followed by vessel
structural expansion54
similar to that seen in the canine model.1
This structural increase in vascular lumen to
normalize shear was prevented in the rat model by
inhibition of nitric oxide synthase (NOS) with N- -nitro-l-arginine-methyl ester.56
The central role of eNOS in shear-mediated
structural remodeling was confirmed by Rudic et
al57
when, in wild-type mice, the common carotid
artery responded to surgically induced decrease
in flow by reducing caliber to normalize shear
stress to its preoperative level, whereas it
failed to do so in mutant mice that lacked the
gene for eNOS.57
In a baboon polytetrafluoroethylene graft fistula
model, elevated shear stress was associated with
increased expression of eNOS, a lower degree of
neointimal and smooth muscle proliferation, and
even induced regression of previously established
neointima.58
In contrast with their high-shear counterparts,
low-shear grafts exhibited greater smooth muscle
cell proliferation and higher levels of platelet-derived
growth factor–A protein and mRNA.59
The connection between high shear stress and low
intimal proliferation has been further clarified
in rodent experiments showing that focal
increases in shear stress in the aorta resulted
in corresponding decreases in angiotensin-converting
enzyme activity.60
Shear
stress has also been associated with the
endothelial proliferative state in animal studies.
Endothelial cell proliferation increased 18-fold
within 48 hours of reduction in shear stress.61
Decreasing shear stress was followed by
endothelial cell loss and desquamation, altered
morphology with decreased elongation, decrease in
actin stress fibers, greater monocyte attachment
to and migration across the endothelial layer,62
and increased endothelial surface expression of
vascular cell adhesion molecule 1.63
The increased endothelial cell loss in response
to decreased shear has recently been suggested to
be the result of apoptosis, which remains
unabated until the shear normalization has been
restored.64
These in vivo experiments obtained in various
species using different methods to alter
hemodynamics help establish a framework to
understand the propensity for intimal hyperplasia
and atherosclerosis initiation in areas of low
shear stress and the protective effect of
elevated shear stress in sheltered regions of the
vasculature.
The
correlations between hemodynamic factors and
intimal hyperplasia in humans and animal models1,
5,
22
have led to intensive study of the in vitro
endothelial response to fluid shear stress in the
past decade.10,
26-30,
65
Short-term
Effects of Shear Stress on Endothelial Function
Hemodynamic shear stress resulting from second-to-minute
time-scale variation in flow increases secretion
of prostacyclin66
and nitric oxide,67,
68
both of which hinder platelet activation,69,
70
attenuate smooth muscle proliferation,71
and inhibit neointima formation following
experimental balloon injury in animals.72,
73
Physiological shear stress (>15 dyne/cm2)
decreases in vitro endothelial cell turnover by
decreasing both the basal rate of proliferation 74,
75
and the rate of apoptosis from growth factor
depletion, tumor necrosis factor  or
hydrogen peroxide exposure 74,
76,
77
via activation of Akt, and attenuated caspase-mediated
killing.76
Control
of Endothelial Gene Expression and Phenotype
Switching by Shear Stress
Fluid shear stress transforms polygonal,
cobblestone-shaped endothelial cells of random
orientation into fusiform endothelial cells
aligned in the direction of flow (Figure
3).
Shear stress of physiological and elevated
magnitudes decreases endothelial turnover by
decreasing both proliferation78
and apoptosis,79,
80
increasing the production of vasodilators,81-87
paracrine growth inhibitors,88
fibronolytics,89-92
and antioxidants,93,
94
and suppressing production of vasoconstrictors,95,
96
paracrine growth promoters,78,
97,
98
inflammatory mediators,99
and adhesion molecules.100,
101
These responses contribute to functional
switching of endothelial phenotype by shear
stress from a quiescent atheroprotective
phenotype under physiological and elevated levels
of shear stress (>15 dyne/cm2) to
an atherogenic phenotype at low shear stress (0-4
dyne/cm2) with high endothelial
turnover. Shear stress thus regulates the
endothelial phenotype on a time scale of hours to
days by controlling the expression of all its
known major functional product classes (Table
1).
Detrimental
Effects of Oscillatory and Turbulent Shear Stress
Oscillatory shear stress, unlike steady shear
stress, can fail to induce [Ca2+]i
transients103
or suppress endothelin 1 mRNA.102
In vitro oscillatory shear stress of low
magnitude (5
dyne/cm2) increases endothelial levels
of superoxide anion (O2-)
via activation of its biosynthetic enzyme,
nicotinamide adenine dinucleotide (reduced form)
oxidase,94
and enhances monocyte adhesion.104
Oscillatory shear stress is a weaker inducer of
eNOS than steady shear stress,105
and creates greater endothelial cell
proliferation.75,
77
Similarly, turbulent shear stress, in contrast to
steady laminar shear stress, induces in vitro
endothelial cell turnover106
and fails to stimulate in vitro mRNA expression
of eNOS, Mn2 + superoxide dismutase,
and COX-2 genes.85
Although
extrapolation from in vitro data to the living
organism may be difficult, these findings suggest
that elevated arterial-level shear stress (>15
dyne/cm2) induces a quiescent,
antiproliferative, antioxidant, and
antithrombotic phenotype,10,
28,
78
while time- and direction-varying low shear
stress magnitude (<4 dyne/cm2), as
seen in regions prone to atherosclerosis,5,
22
results in an aggressive and proliferative
phenotype.
A
Model of Atherogenesis Based on the Endothelial
Response to Shear Stress
Investigations of the cellular mechanisms of
atherosclerosis initiation and progression have
contributed to a consistent model involving
immune and inflammatory responses perpetuated by
a self-reinforcing cycle of monocyte recruitment,
lipid accumulation by macrophages, increased
smooth muscle cell proliferation, increased
oxidant activity, and eventual plaque rupture and
thromboembolic complications.37,
107
The paradigm of endothelial functional regulation
by shear stress can explain the focal propensity
of the atherosclerotic response to intimal injury
(Figure
2
and Figure
4
and Table
1).
The
shear-controlled gene expression of endothelial
cells likely has evolved to maintain global
vascular structural and functional homeostasis
through local control by transduction of
hemodynamic shear. Shear stress of physiological
arterial magnitudes (>15 dyne/cm2)
appears to produce an atheroprotective
endothelial phenotype (Figure
3
and Figure
4)
that consists of decreased expression of
vasoconstrictors, paracrine growth factors,
inflammatory mediators, adhesion molecules,
oxidants, and elevated production of vasodilators,
growth inhibitors, fibrinolytics, antiplatelet
factors, and antioxidants. The atheroprotective
phenotype is imparted by physiological and
elevated shear and renders endothelium less
susceptible to pathogenic stimuli of injury, cell
adhesion, cell proliferation, and lipid uptake (Figure
4).
In
contrast, the outer walls of vessel bifurcations
are characterized by low and oscillatory shear
stress due to vascular network architectural
constraints (04
dyne/cm2) and are prone to
atherosclerosis. These focal areas manifest
greater endothelial cell cycling and
vulnerability to systemic apoptogenic stimuli
such as oxidized low-density lipoprotein and
tumor necrosis factor (TNF) .
Endothelial cells under the hemodynamic
conditions described in Figure
4
might preferentially activate circulating
monocytes and encourage local adhesion and
diapedesis. Persistently low antioxidant levels
likely act in synergy with reduced production of
nitric oxide to potentiate the steady paracrine
mitogenic stimulation of vessel wall constituents.
High endothelial production of vasoconstrictor
and mitogenic substances such as endothelin 1,
angiotensin II, and platelet-derived growth
factor B acts to perpetuate underlying smooth
muscle and fibroblast proliferation. In addition,
reduced production of fibrinolytic tissue-type
plasminogen activator, coupled with low
production of nitric oxide and prostacyclin, may
foster focal platelet aggregation and fibrin
deposition, accelerating plaque formation and
increasing the risk of thromboembolic events.
This hypothesis is compatible with systemic
effects of hyperlipidemia on blood viscosity,108
and with possible effects of low blood flow on
increased platelet aggregation109
and thrombosis.110
This
model does not preclude the important
contributions of known systemic cardiovascular
risk factors. These deleterious systemic factors,
such as smoking, hyperlipidemia, hypertension, or
infectious agents, although thought to act on all
regions of the vasculature, may be particularly
potent in accentuating the local atherogenic
phenotype of the endothelial cell in regions of
low shear stress. Similarly, the systemic
benefits of exercise, such as the observed
increase in human NOS activity with cycle
training,111
may induce local elevations of atheroprotective
shear stress at otherwise atherosclerosis-prone
low-flow regions at bifurcations. Sufficient
activity-related elevation of local shear stress
might then shift endothelial phenotype along the
continuum from atherogenic toward
atheroprotective, thus attenuating (and
potentially reversing) this chronic disease
process.
CONCLUSION
Shear
stress studies have altered our concept of the
endothelium from that of a passive,
nonthrombogenic surface to that of a dynamically
responsive vascular element producing autocrine
and paracrine factors under the functional
regulation of local hemodynamic forces.10,
26-30,
65
These findings have underlined the importance of
studying endothelial cell function under flow
conditions and have renewed efforts to identify
novel and known gene products that may be
regulated by shear stress.85,
112
The molecular phenotypic switching of endothelium
by shear stress offers an integrated model to
explain the focal nature of atherosclerosis.
Future work will address therapeutic approaches
to thwart the local atherogenic phenotype of the
endothelial cell in lesion-prone low-shear
regions, without interfering with its ability to
maintain global vascular homeostasis, and should
include studies of interactions of this
regulation by clinically established
cardiovascular risk factors.
Author/Article
Information
Author Affiliations: Neurosurgery, Brigham
and Women's Hospital and Children's Hospital (Dr
Malek), and Departments of Neurosurgery (Dr Malek),
Medicine (Drs Alper and Izumo), and Cell Biology
(Dr Alper), Harvard Medical School, and Molecular
Medicine and Renal Units (Dr Alper), and
Cardiovascular Division (Dr Izumo), Beth Israel
Deaconess Medical Center, Boston, Mass; and
Division of Interventional Neurovascular
Radiology, University of California at San
Francisco, San Francisco (Dr Malek).
Corresponding Author and Reprints: Adel M.
Malek, MD, PhD, Neurosurgery, Brigham and Women's
and Children's Hospitals, Bader 3, 300 Longwood
Ave, Boston, MA 02115 (e-mail: ammalek@bics.bwh.harvard.edu).
Funding/Support:
Dr Malek was supported by a National Institutes
of Health (NIH) Medical Scientist Training
Program grant, the Whitaker Foundation, and the
Boston Neurosurgical Foundation. Dr Alper is
supported by NIH grant HL15175 and by a grant-in-aid
from the American Heart Association. Drs Izumo
and Alper were Established Investigators of the
American Heart Association during the course of
this research.
Acknowledgment:
We apologize to those colleagues whose work was
not cited due to space limitations.
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