Arterial compliance and endothelial function

Abstract

Decreased arterial compliance (increased stiffness) correlates with cardiovascular events, possibly due to increased cardiac afterload caused by more rapidly reflected pulse waves. Endothelium-derived mediators regulate vascular tone and structure, both of which can markedly influence arterial stiffness. Thus, increased arterial stiffness may be a mechanism by which endothelial dysfunction predisposes to complications of atherosclerosis. Conversely, therapeutic manipulation of endothelial mediators could reduce arterial stiffness and cardiovascular events. Techniques have been developed that use measures of arterial stiffness as an index of endothelial dilator function; these may provide unique prognostic information to identify high-risk subjects.

Full text

A
rteria
l
Comp
l
iance an
d
En
dothel
i
al
F
u
n
ct
i
on
Marcelo L.G. Correia, MD, and William G. Haynes, M
D
C
orrespon
d
ing aut
h
o
r
M
arcelo L.G. Correia, M
D
G
eneral Clinical Research Center (157 MRF), 200 Hawkins Drive,
U
niversit
y
o
f
Iowa, Iowa Cit
y
, IA, 52242, USA
.
E-mail: marcelo-correia@uiowa.ed
u
C
urrent Dia
b
etes Reports 2007,
7:
269
–
2
7
5
Current Me
d
icine Grou
p
LLC ISSN 1534-482
7
Copyright © 2007 by Current Medicine Group LLC
Decreased arterial compliance (increased stiffness)
c
orre
l
ates wit
h
car
d
iovascu
l
ar events,
p
ossi
bly
d
ue to
increased cardiac afterload caused b
y
more ra
p
idl
y
r
eflected pulse waves. Endothelium-derived mediators
r
e
g
ulate vascular tone and structure, both o
f
which can
m
arkedl
y
influence arterial stiffness. Thus, increased
a
rterial stiffness may be a mechanism by which end
o
-
thelial d
y
s
f
unction
p
redis
p
oses to com
p
lications o
f
a
therosclerosis. Conversel
y
, thera
p
eutic mani
p
ulation of
e
ndothelial mediators could reduce arterial stiffness and
c
ar
d
iovascu
l
ar events. Tec
h
ni
q
ues
h
ave
b
een
d
eve
l
o
p
e
d
t
h
at
use
m
easu
r
es
o
f
a
r
te
ri
a
l
st
iffn
ess
as
a
n in
de
x
o
f
e
ndothelial dilator function; these may provide unique
pro
g
nostic in
f
ormation to identi
f
y hi
g
h-risk sub
j
ects
.
Intro
d
uction
Th
e comp
l
iance o
f
arteries
d
ecreases (ie, sti
ff
ness
increases) wit
h
aging an
d
in severa
l
d
iseases, suc
h
as o
be
-
sit
y
, h
yp
ertension, diabetes, chronic kidne
y
disease, and
at
h
erosc
l
erosis. O
f
note, increase
d
arteria
l
sti
ff
ness is an
in
d
e
p
en
d
ent ris
k
f
actor
f
or car
d
iovascu
l
ar
d
isease [1,2]
and is associated with increased cardiovascular mortalit
y
[3]. T
h
e mec
h
anism
f
or t
h
is association is not comp
l
ete
l
y
c
l
ear. One possi
b
i
l
ity is t
h
at increase
d
arteria
l
sti
ff
ness
is a marker for earl
y
atherosclerosis, without necessaril
y
h
aving
d
irect a
d
verse consequences. However, t
h
ere is
also
ev
i
de
n
ce
that
in
c
r
eased
a
r
te
ri
al
st
i
ff
n
ess
ca
n
cause
a more ra
p
id return of the reected s
y
stolic wave from
sma
ll
perip
h
era
l
vesse
l
s, suc
h
t
h
at t
h
is augments centra
l
aortic systo
l
ic pressure. T
h
is wou
ld
t
h
en increase car
d
iac
afterload and, throu
g
h reduced diastolic
p
ressure, reduce
coronary per
f
usion pressure. T
h
us, increase
d
arteria
l
sti
ff
-
ness cou
ld
d
irect
l
y contri
b
ute to myocar
d
ia
l
h
ypertrop
h
y,
ischemia, and infarction [4]. This conce
p
t is su
pp
orted b
y
th
e
f
act t
h
at centra
l
aortic rat
h
er t
h
an perip
h
era
l
bl
oo
d
p
ressure (BP) is more c
l
ose
l
y associate
d
wit
h
car
d
iovascu
-
lar risk
[
5••
]
.
Arteria
l
sti
ff
ness is in

uence
d
b
y severa
l
f
actors t
h
at
regu
l
ate t
h
e static an
d
d
ynamic properties o
f
t
h
e arteria
l
v
essels. Static com
p
onents are related to the architecture
an
d
composition o
f
t
h
e arteria
l
wa
ll
suc
h
as t
h
e t
h
ic
k
ness
o
f
t
h
e me
d
ia an
d
a
d
ventitia, an
d
t
h
e t
yp
e an
d
content o
f
colla
g
en and elastin in the extracellular matrix. D
y
namic
f
actors are main
l
y re
l
ate
d
to vascu
l
ar tone an
d
regu
l
ate
d
by
p
aracrine, en
d
ocrine, an
d
neura
l
mec
h
anisms. En
d
o
-
t
helium-derived com
p
ounds, such as nitric oxide (NO),
e
n
d
ot
h
e
l
ium-
d
erive
d
h
yperpo
l
arizing
f
actors (EDHFs),
p
rosta
gl
an
d
ins, an
d
en
d
ot
h
e
l
ins (ETs),
pl
a
y
a ma
j
or ro
l
e
in the d
y
namic re
g
ulation of vascular tone and BP, and
appear to important
l
y mo
d
u
l
ate t
h
e state o
f
arteria
l
sti
ff
-
ness. We review
b
ot
h
structura
l
an
d
dy
namic e
ff
ects o
f
e
ndothelial-de
p
endent factors on arterial stiffness, with
e
mp
h
asis on t
h
e actions o
f
NO.
Techniques to Measure Arterial Stiffnes
s
Severa
l
tec
h
niques
h
ave
b
een
d
eve
l
ope
d
to assess art
e
-
rial stiffness. Perha
p
s the sim
p
lest is
p
ulse
p
ressure (PP;
b
rac
h
ia
l
systo
l
ic BP -
d
iasto
l
ic BP). Sti
ff
ene
d
l
arge arteries
increase PP t
h
roug
h
a re
d
uction in arteria
l
comp
l
iance
with effects on wave reection
[
6
]
. However, PP calculated
f
rom perip
h
era
l
BP rea
d
ings may not re
l
ia
bl
y re

ect ce
n
-
t
ra
l
PP [7]. Pu
l
se wave ve
l
ocity (PWV) is a measurement
of arterial stiffness that com
p
utes the velocit
y
of
p
ro
p
a
g
a
-
t
ion o
f
t
h
e arteria
l
pu
l
se
f
rom a proxima
l
to a
d
ista
l
site
over a
k
nown
d
istance an
d
time. T
yp
ica
lly
, simu
l
taneous
e
valuation of
p
ulse wave at the carotid and femoral arter
-
ies pro
d
uces va
l
i
d
estimates o
f
t
h
e PWV, w
h
ic
h
re

ects
st
i
ff
a
r
te
ri
es
whe
n in
c
r
eased.
An alternative a
pp
roach is to use
p
ulse wave contour
ana
l
ysis to in
d
irect
l
y estimate t
h
e position o
f
t
h
e re

ecte
d
arteria
l
wave in t
h
e centra
l
aorta. As mentione
d
b
e
f
ore,
t
he s
y
stolic arterial wave
p
ro
p
a
g
ates from the low-im
p
ed
-
ance centra
l
arteries to t
h
e
h
ig
h
-impe
d
ance perip
h
era
l
circu
l
ation an
d
t
h
en generates a re

ection wave t
h
at tra
v
-
e
ls back toward the heart, increasin
g
the overall
p
ressure
in t
h
e centra
l
arteries. Grap
h
ica
ll
y, t
h
e re

ection wave is
superimpose
d
on t
h
e
f
orwar
d
wave an
d
creates t
h
e systo
l
ic
notch found on a t
yp
ical arterial
p
ulse tracin
g
. If we co
n
-
si
d
er t
h
e maxima
l
h
eig
h
t o
f
t
h
e
f
orwar
d
wave measure
d
at

2
70
E
n
d
ot
h
e
l
ia
l
D
y
s
f
unction
t
he radial arter
y
as P1 and that of the reection wave as
P2 (Fig. 1), t
h
e ra
d
ia
l
(or perip
h
era
l
) augmentation in
d
ex
(AI) is
d
e

ne
d
as P2/P1. T
h
e am
pl
i

cation o
f
t
h
e re

ection
wave due to increased arterial stiffness increases P2 and
consequent
l
y t
h
e AI. T
h
e centra
l
AI is ca
l
cu
l
ate
d
simi
l
ar
l
y
b
ut a
l
so ta
k
es into account t
h
e
d
iasto
l
ic com
p
onent o
f
t
h
e
aortic
p
ulse wave [8]. Central AI can be derived directl
y
f
rom aortic pressure wave
f
orms or, more common
l
y, in
d
i
-
rect
ly
estimate
d
f
rom a
lg
orit
h
ms t
h
at convert ra
d
ia
l
or
carotid
p
ulse waveforms. It is noteworth
y
that increased
aortic AI
h
as
b
een associate
d
wit
h
arteria
l
sti
ff
ness an
d
its c
l
inica
l
consequences [9].
Lar
g
e arter
y
distensibilit
y
and com
p
liance also directl
y
re

ect arteria
l
sti
ff
ness an
d
are
d
e

ne
d
as t
h
e re
l
ative an
d
a
b
so
l
ute c
h
ange in vesse
l
d
iameter or area
f
or a given
chan
g
e in
p
ressure, res
p
ectivel
y
. Thus, the measurement
o
f
incrementa
l
pressures an
d
t
h
e
d
iameter or area o
f
t
h
e
artery o
f
interest is necessary
f
or t
h
e ca
l
cu
l
ation o
f
arteria
l
distensibilit
y
and com
p
liance. T
yp
icall
y
, these
p
arameters
are measure
d
b
y caroti
d
u
l
trasoun
d
an
d
app
l
anation
t
onometry. Nevert
h
e
l
ess, it is not possi
bl
e to measure t
h
e
absolute carotid BPs, which are instead calculated usin
g
th
e caroti
d
wave
f
orm an
d
b
rac
h
ia
l
artery mean arteria
l
p
ressure
[
10
].
D
y
namic Re
g
u
l
ation o
f
Arteria
l
Sti
ff
ness:
T
h
e Ro
l
e o
f
N
O
Severa
l
stu
d
ies provi
d
e evi
d
ence
f
or a ro
l
e o
f
en
d
ot
h
e
l
ia
l
f
actors on t
h
e regu
l
ation o
f
arteria
l
d
istensi
b
i
l
ity an
d
stiffness in animals and humans. As s
p
ontaneousl
y
h
yp
er
-
t
ensive rats (SHRs) age, t
h
ey ex
h
i
b
it a
d
isproportionate
increase in PP re
l
ative to mean BP, w
h
ic
h
re

ects sti
ff
er
arteries. Vascular ri
g
idit
y
with a
g
in
g
could be attributed
so
l
e
l
y to structura
l
c
h
anges in arteries
f
rom o
ld
SHRs.
However, aging a
l
so c
h
anges en
d
ot
h
e
l
ia
l
mo
d
u
l
ation o
f
v
ascular tone. For exam
p
le, removal of the endothelium
f
rom aortic rings o
f
o
ld
SHRs
d
oes not su
b
stantia
ll
y
chan
g
e the contractile res
p
onse to noradrenaline, whereas
suc
h
a response is signi

cant
l
y augmente
d
in aortic rings
f
rom young SHRs. O
ld
er SHRs ex
h
i
b
it
d
ecrease
d
so
l
u
bl
e
g
uan
y
l
y
l c
y
clase in aortic tissue, su
gg
estin
g
reduced NO
action [11]. Important
l
y, NO reconstitution in o
ld
SHRs
acute
l
y norma
l
izes t
h
e
d
isproportionate increase in PP,
without effects on arterial architecture or mean BP
[
12
]
.
Th
ese resu
l
ts suggest t
h
at coup
l
ing
b
etween t
h
e en
d
ot
he
-
l
ium an
d
vascu
l
ar smoot
h
musc
l
e cou
ld
b
e an important
dete
rmin
a
n
t
o
f
a
r
te
ri
a
l
st
iffn
ess.
M
ore
d
irect evi
d
ence
f
or coup
l
ing
b
etween en
d
ot
h
e
l
ia
l
f
unction an
d
arteria
l
sti
ff
ness
h
as
b
een
d
escri
b
e
d
in s
h
eep.
W
ilkinson et al.
[
7
]
demonstrated that local inhibition
o
f
NO synt
h
ase (t
h
roug
h
intra-arteria
l
N
G
monomet
h
y
l-
L
-arginine [L-NMMA]) acute
l
y increase
d
common i
l
iac
arter
y
PWV, whereas acet
y
lcholine and nitrates decreased
it. Important
l
y, intra-arteria
l
L-NMMA
bl
unte
d
t
h
e
b
e
n
-
e
cia
l
e
ff
ect o
f
acet
yl
c
h
o
l
ine on arteria
l
sti
ff
ness, wit
h
out
alterin
g
res
p
onses to nitrates or s
y
stemic arterial
p
ressure.
Upstream vasoconstriction cou
ld
h
ave contri
b
ute
d
to t
h
is
res
p
onse. However,
d
ista
l
intra-arteria
l
in
f
usions o
f
L
-
NMMA or acet
y
lcholine did not chan
g
e PWV [7]
.
S
evera
l
l
ines o
f
evi
d
ence support an association
betwee
n
a
r
te
ri
al
st
i
ff
n
ess
a
n
d
e
n
dothel
i
al
fu
n
ct
i
o
n in
humans. In h
yp
ertensive and normotensive sub
j
ects,
impaire
d
coronary vaso
d
i
l
atation to acety
l
c
h
o
l
ine cor
-
re
l
ates wit
h
am
b
u
l
ator
y
PP [13,14]. PP was t
h
e stron
g
est
p
redictor of endothelial d
y
sfunction in untreated h
yp
er
-
t
ension [15]. A
l
so, PWV invasive
l
y measure
d
at t
h
e i
l
iac
artery
d
ecreases in response to acety
l
c
h
o
l
ine in
h
ea
l
t
h
y
sub
j
ects, but not in
p
atients with con
g
estive heart failure
[16]. In a
dd
ition, noninvasive measurements o
f
PWV
negative
l
y corre
l
ate wit
h
t
h
e en
d
ot
h
e
l
ia
l
f
unction in
E
-thalassemia ma
j
or [17]. Finall
y
, both brachial arter
y
e
n
d
ot
h
e
l
ia
l
d
ys
f
unction an
d
increase
d
AI corre
l
ate wit
h
increase
d
caroti
d
intima-me
d
ia t
h
ic
k
ness
[
18
].
The ma
j
orit
y
of
p
artici
p
ants in studies evaluatin
g
the
re
l
ations
h
ips
b
etween en
d
ot
h
e
l
ia
l
f
unction an
d
arteria
l
sti
ff
ness were eit
h
er at ris
k
f
or or presente
d
overt car
-
diovascular disease that could confound such anal
y
ses.
Add
ressing t
h
is issue, McEniery et a
l
. [19••]
d
emonstrate
d
th
at en
d
ot
h
e
l
ia
l
f
unction is a
l
so consistent
ly
an
d
ne
ga
-
t
ivel
y
correlated with PWV and AI in health
y
sub
j
ects. In
th
is popu
l
ation, age an
d
en
d
ot
h
e
l
ia
l
f
unction accounte
d
f
or 7% an
d
14% o
f
t
h
e varia
b
i
l
ity o
f
aortic PWV, respec
-
t
ivel
y
, after ad
j
ustments for diverse demo
g
ra
p
hic and
h
emo
d
ynamic varia
bl
es. T
h
us, t
h
e contri
b
ution o
f
en
d
o
-
th
e
l
ia
l
f
unction to arteria
l
sti
ff
ness appears to
b
e mo
d
est
in health
y
low-risk human sub
j
ects
.
I
t is unc
l
ear
f
rom t
h
ese cross-sectiona
l
stu
d
ies w
h
et
h
er
e
n
d
ot
h
e
l
ia
l
d
ys
f
unction is a cause or a consequence o
f
increased lar
g
e arter
y
stiffness in humans. This im
p
ortant
question
h
as
b
een a
dd
resse
d
in p
h
armaco
l
ogic stu
d
ies.
Important
l
y, intra-arteria
l
in
f
usion o
f
L-NMMA causes
dose-de
p
endent acute increases in PWV directl
y
measured
in t
h
e i
l
iac artery o
f
su
b
jects un
d
ergoing
d
iagnostic car
-
Pressure, mm
H
g
Ti
me,
ms
ec
P1
P2
Fi
gure 1. Pulse wave o
f
the brachial arter
y
. P1 denotes the s
y
stolic
outwar
d
pressure, w
h
ereas P2 in
d
icates t
h
e
h
i
gh
est pressure
d
erive
d
f
rom the reflection wave
.

A
rteria
l
Com
pl
iance an
d
En
d
ot
h
e
l
ia
l
Functio
n
C
orreia an
d
Ha
y
nes 2
71
diac catheterization
,
whereas nitrate infusion decreases
PWV, in
d
epen
d
ent o
f
c
h
anges in BP [20••]. T
h
ere
f
ore,
it appears
l
i
k
e
l
y t
h
at en
d
ot
h
e
l
ia
l
d
ys
f
unction can acute
l
y
p
roduce arterial stiffenin
g
.
I
ntriguing
l
y, t
h
ere is a
l
so evi
d
ence
f
or t
h
e reverse ass
o
-
ciation. En
d
ot
h
e
l
ia
l
ce
ll
cu
l
tures su
b
jecte
d
to p
h
asic s
h
ear
and stretch manifest increased
p
hos
p
hor
y
lation of serine-
th
reonine
k
inase A
k
t t
h
at resu
l
ts in increase
d
expression
o
f
NO synt
h
ase. T
h
e a
b
i
l
ity o
f
en
d
ot
h
e
l
ia
l
ce
ll
s to express
NO s
y
nthase while in stiff tubes is substantiall
y
reduced.
Th
ese resu
l
ts suggest t
h
at t
h
e sti
ff
ening o
f
t
h
e arteries
cou
ld
aggravate en
d
ot
h
e
l
ia
l
d
ys
f
unction [21]. T
h
ere
f
ore,
conce
p
tuall
y
it is
p
ossible that endothelial d
y
sfunction
cou
ld
contri
b
ute to t
h
e ear
l
y stages o
f
arteria
l
sti
ff
ening,
w
h
ic
h
cou
ld
t
h
en
f
urt
h
er aggravate en
d
ot
h
e
l
ia
l
d
ys
f
unc
-
t
ion in a vicious c
y
cle.
Structura
l
Determinants o
f
Arteria
l
Sti
ff
ness:
Th
e
R
o
l
e
o
f N
O
NO-
d
e
p
en
d
ent mec
h
anisms can
p
romote vascu
l
ar remo
d
-
e
lin
g
directl
y
throu
g
h actions on the extracellular matrix
and cellular com
p
onents of the blood vessel. The ant
i
-
p
ro
l
i
f
erative e
ff
ect o
f
NO
h
as
b
een we
ll
esta
bl
is
h
e
d
b
ot
h
in vivo and in vitro. Overex
p
ression of NO s
y
nthase sub
-
stantia
ll
y attenuates
f
ormation o
f
neointima
l
tissue a
f
ter
v
ascu
l
ar in
j
ur
y
[22]. P
h
armaco
l
o
g
ic or
g
enetic NO
d
onors
inhibit vascular smooth cell
p
roliferation [23,24]
.
C
yc
l
in-
d
epen
d
ent
k
inases (c
dk
s) regu
l
ate t
h
e progre
s
-
sion o
f
t
h
e ce
ll
cyc
l
e. Progression into t
h
e G1 p
h
ase an
d
initiation of the S
p
hase is
p
romoted b
y
the interaction
o
f
c
dk
2 wit
h
cyc
l
ins E an
d
A [25]. NO regu
l
ates
k
ey c
dk
in
h
i
b
itors an
d
t
h
e activity o
f
cyc
l
in E an
d
A
k
inases. T
h
e
t
r
eat
m
e
n
t
o
f h
u
m
a
n
ao
r
t
i
c
vascu
l
a
r
s
m
oot
h m
usc
l
e
ce
ll
s
wit
h
NO
d
onors arrests t
h
e G1 ce
ll
cyc
l
e. T
h
is e
ff
ect is
main
l
y attri
b
ute
d
to in
h
i
b
ition o
f
c
dk
2 an
d
cyc
l
in A
e
x
p
ression, whereas the ex
p
ression of the cdk inhibitors
p
21 an
d
p27 is increase
d
, in
d
epen
d
ent
l
y o
f
apoptotic
p
rocesses [25,26]. T
h
ere
f
ore, re
d
uce
d
b
ioavai
l
a
b
i
l
ity o
f
NO that occurs durin
g
endothelial d
y
sfunction could
p
otentia
ll
y
b
e associate
d
wit
h
su
b
stantia
l
re
d
uctions in
anti
p
ro
l
i
f
erative si
g
na
l
s an
d
t
h
us
p
romote intima
l
an
d
v
ascular smooth muscle cell h
yp
ertro
p
h
y
, increasin
g
art
e
-
ria
l
sti
ff
ness
.
I
ncrease
d
arteria
l
sti
ff
ness cou
ld
b
e
f
urt
h
er aggra
-
v
ated b
y
alteration of extracellular matrix com
p
onents in
th
e vascu
l
ar wa
ll
. T
h
e extrace
ll
u
l
ar matrix is main
l
y co
m
-
p
ose
d
o
f
co
ll
agen an
d
e
l
astin t
h
at are
d
egra
d
e
d
b
y matrix
metallo
p
roteinases (MMPs). Tissue inhibitors of MMPs
counter t
h
is response, contro
ll
ing remo
d
e
l
ing [27••].
Nota
bl
y, NO
h
as
b
een s
h
own to regu
l
ate MMP expre
s
-
sion in both conduit and resistance vessels. For instance
,
arteriovenous

stu
l
as are associate
d
wit
h
tears in t
h
e
interna
l
e
l
astic
l
amina wit
h
ensuing activation o
f
MMPs
and conduit vascular remodelin
g
. In rabbits, carotid-
j
u
gu
-
l
ar

stu
l
as su
b
stantia
ll
y increase MMP-2 an
d
-9 activity,
an effect that is attenuated b
y
inhibition of NO s
y
nthase
[28]. A
dd
itiona
ll
y, experimenta
ll
y increasing mesenteric
artery
bl
oo
d

ow causes outwar
d
h
ypertrop
h
ic remo
d
e
l
-
in
g
with increased ex
p
ression of endothelial NO s
y
nthase
an
d
MMP-9 activity. T
h
is vascu
l
ar remo
d
e
l
ing can
b
e
p
revente
d
b
y t
h
e MMP in
h
i
b
itor
d
oxycyc
l
ine an
d
a
l
so
b
y
p
harmacolo
g
ic inhibition and
g
ene knockout of endoth
e
-
l
ia
l
NO synt
h
ase [29•]
.
O
vera
ll
, overexpression o
f
NO synt
h
ase in response to
increased blood ow a
pp
ears to acutel
y
p
roduce com
p
e
n
-
satory vascu
l
ar remo
d
e
l
ing t
h
at temporari
l
y norma
l
izes
s
h
ear stress
f
orces acting on t
h
e arteria
l
wa
ll
o
f
con
d
uit
and resistance arteries. It is likel
y
that endothelial factors
ot
h
er t
h
an NO mig
h
t a
l
so contri
b
ute to vascu
l
ar remo
d
-
el
ing. T
h
e
d
eve
l
opment o
f
en
d
ot
h
e
l
ia
l
d
ys
f
unction in
res
p
onse to risk factors likel
y
causes abnormal structural
v
ascu
l
ar remo
d
e
l
ing t
h
roug
h
ce
ll
u
l
ar an
d
extrace
ll
u
l
ar
matrix actions, t
h
ere
by
increasin
g
arteria
l
sti
ff
ness in
co
n
du
i
t
a
n
d
r
es
i
sta
n
ce
vesse
l
s.
T
h
e interaction
b
etween NO an
d
MMPs may span
b
e
y
on
d
e
ff
ects on extrace
ll
u
l
ar matrix. MMP-2 an
d
MMP-
9
p
romote the dilation of aortic rin
g
s from S
p
ra
g
ue-Dawle
y
rats
b
y in
h
i
b
iting ca
l
cium in

ux into vascu
l
ar smoot
h
musc
l
e
[
30•
]
. A
l
so, MMP-2
h
as
b
een s
h
own to
d
i
l
ate iso
-
lated veins from S
p
ra
g
ue-Dawle
y
rats throu
g
h activation
o
f
ca
l
cium-
d
epen
d
ent potassium c
h
anne
l
s [31]. T
h
ere
f
ore,
e
n
d
ot
h
e
l
ia
l
dy
s
f
unction mi
gh
t
d
ownre
g
u
l
ate t
h
e activit
y
o
f
M
MP-2 and -9
,
which could cause vasoconstriction.
A
rteria
l
Sti
ff
ness an
d
Ot
h
er En
d
ot
h
e
l
ia
l
Factor
s
In a
dd
ition to NO, t
h
e en
d
ot
h
e
l
ium secretes ot
h
er
f
a
c
-
t
ors t
h
at contri
b
ute to t
h
e regu
l
ation o
f
vascu
l
ar tone in
h
u
m
a
n
co
n
du
i
t
a
n
d
r
es
i
sta
n
ce
a
r
te
ri
es.
Thr
ee
f
acto
r
s
h
ave
b
een exp
l
ore
d
in
d
ept
h
: prostacyc
l
in, EDHFs, an
d
ETs
.
P
rostacyc
l
in is
d
erive
d
f
rom en
d
ot
h
e
l
ia
l
cyc
l
ooxygen
-
ase (COX) action on arachidonic acid and increases c
y
clic
A
MP to cause vaso
d
i
l
ation [32]. However, prostacyc
l
in
apparent
l
y p
l
ays no ro
l
e in ra
d
ia
l
artery en
d
ot
h
e
l
ium-
de
p
endent dilation in health
y
sub
j
ects, su
gg
estin
g
that
p
rostacyc
l
in may not contri
b
ute to t
h
e p
h
ysio
l
ogic regu
la
-
t
ion o
f
vascu
l
ar tone in con
d
uit arteries
[
33
]
. In
l
ine wit
h
t
his inter
p
retation, it is im
p
ortant to note that nonselec
-
t
ive COX antagonism
h
as no e
ff
ect on BP in
h
umans [32].
Nevert
h
e
l
ess, increasing t
h
e
l
eve
l
s o
f
prostacyc
l
in rece
p
-
t
or stimulation throu
g
h administration of bera
p
rost, a
p
rostacyc
l
in ana
l
ogue, su
b
stantia
ll
y re
d
uce
d
PWV a
f
ter
3
mont
h
s o
f
treatment in e
ld
er
l
y su
b
jects wit
h
cere
b
ra
l
ischemia. This result su
gg
ests that the
p
harmacolo
g
ic
d
oses o
f
prostacyc
l
in can
h
ave e
ff
ects on vascu
l
ar sti
ff
-
ness an
d
cou
ld
b
e a t
h
erapeutic approac
h
to prevent
v
ascular disease [34]. Interestin
g
l
y
, endothelium-derived
p
rostag
l
an
d
ins
f
aci
l
itate

ow-me
d
iate
d
d
i
l
ation in
N
Z
-
nitro-L-arginine met
h
y
l
ester–treate
d
rats an
d
in mice
with endothelial NO s
y
nthase
g
ene knockout [35,36].
Th
ere
f
ore, it is conceiva
bl
e t
h
at increase
d
vascu
l
ar ge
n
-

2
7
2
E
n
d
ot
h
e
l
ia
l
D
y
s
f
unction
e
ration or activit
y
of
p
rostac
y
clin mi
g
ht com
p
ensate for
re
d
uce
d
NO
b
ioavai
l
a
b
i
l
ity
.
EDHFs reporte
dl
y cause vaso
d
i
l
ation t
h
roug
h
severa
l
mechanisms, includin
g
o
p
enin
g
of
p
otassium channels,
increase
d
en
d
ot
h
e
l
ia
l
generation o
f
h
y
d
rogen peroxi
d
e
an
d
epoxyeicosatrienoic aci
d
s (EETs), an
d
ion exc
h
ange
across
g
a
p
j
unctions linkin
g
endothelial and vascular
smoot
h
musc
l
e ce
ll
s [37,38]. In
h
ea
l
t
h
y su
b
jects, maxima
l
an
d
sustaine
d

ow-me
d
iate
d
con
d
uit artery
d
i
l
ation is
decreased b
y
L-NMMA, tetraeth
y
lammonium (a Ca
2+
-
activatate
d
potassium c
h
anne
l
in
h
i
b
itor), an
d

uconazo
l
e
(cytoc
h
rome P450 epoxygenase in
h
i
b
itor) [39]. Overa
ll
,
t
his stud
y
demonstrates that NO and EETs are involved in
con
d
uit artery

ow-me
d
iate
d
d
i
l
atation in
h
ea
l
t
h
y
h
umans
d
uring sustaine
d

ow con
d
itions. A
d
irect e
ff
ect o
f
EDHF
on arterial stiffness has not been documented. However
,
it was s
h
own t
h
at EETs act as a compensatory mec
h
anism
t
o sustain en
d
ot
h
e
l
ium-
d
e
p
en
d
ent vaso
d
i
l
ation in
hyp
er
-
t
ensive sub
j
ects with endothelial d
y
sfunction [40]. This
o
b
servation a
l
so suggests t
h
at EETs cou
ld
potentia
ll
y
attenuate arteria
l
sti
ff
enin
g
associate
d
wit
h
hyp
ertension
.
ETs (ET-1 throu
g
h ET-3) are a famil
y
of 21 amino acid
p
epti
d
es wit
h
important vascu
l
ar actions. ET-1 is t
h
e pre
-
d
ominant vascu
l
ar iso
f
orm an
d
acts on s
p
eci

c vascu
l
ar
smooth muscle endothelin A and B rece
p
tors (ETA/ETB)
t
o potent
l
y e
l
icit vasoconstriction. Acting on ETB receptors
l
ocate
d
on en
d
ot
h
e
l
ia
l
ce
ll
s, ET-1 can a
l
so in
d
uce vaso
d
i
la
-
t
ion throu
g
h NO and
p
rostac
y
clin-de
p
endent mechanisms
[41]. Important
l
y, intra-arteria
l
a
d
ministration o
f
ET-1
acute
l
y increases PWV
d
irect
l
y measure
d
in t
h
e i
l
iac artery
of the shee
p
, whereas ETA rece
p
tor blockade decreases
PWV [42]. T
h
is
l
ast

n
d
ing supports an important ro
l
e
f
or
e
n
d
ogenous ET-1 generation in t
h
e p
h
ysio
l
ogic regu
l
ation
of arterial ri
g
idit
y
in the shee
p
. This result also corrob
o
-
rates t
h
e o
b
servation t
h
at increase
d
p
l
asma ET-1
l
eve
l
s
corre
l
ate wit
h
increase
d
con
d
uit artery sti
ff
ness in
h
umans
with coronar
y
arter
y
disease [43]
.
I
n a
dd
ition, ET-1 is invo
l
ve
d
wit
h
c
h
ronic vascu
l
ar
remo
d
e
l
ing
b
ecause activation o
f
vascu
l
ar smoot
h
musc
l
e
cell ETA/ETB rece
p
tors causes vascular h
yp
ertro
p
h
y
and
h
yperp
l
asia. In anima
l
s, ET-1
h
as
b
een associate
d
wit
h
neointima
l
f
ormation a
f
ter vascu
l
ar in
j
ur
y
, w
h
ereas ET
rece
p
tor anta
g
onism
p
revents vascular remodelin
g
in ex
p
e
r
-
imenta
l
h
ypertension [44]. T
h
us, ETs cou
ld
contri
b
ute to
b
ot
h
structura
l
an
d
d
ynamic aspects o
f
arteria
l
sti
ff
ness
.
C
l
inica
l
Im
pl
ications o
f
Arteria
l
Sti
ff
ness
Caused by Endothelial Dysfunction
Severa
l
epi
d
emio
l
ogic stu
d
ies report t
h
at increase
d
art
e
-
ria
l
sti
ff
ness is an in
d
epen
d
ent car
d
iovascu
l
ar ris
k
f
actor.
For exam
p
le, au
g
mented PP is associated with increased
a
ll
-cause an
d
car
d
iovascu
l
ar morta
l
ity among normoten
-
sive an
d
h
ypertensive su
b
jects in France [45,46], w
h
ic
h
was further corroborated b
y
ndin
g
s from the Framin
g
-
h
am Heart Stu
d
y [47]. Furt
h
ermore, increase
d
PWV was
an inde
p
endent
p
redictor of cardiovascular mortalit
y
in
a
l
arge c
l
inic-
b
ase
d
popu
l
ation o
f
h
ypertensive su
b
jects
an
d
in patients wit
h
en
d
-stage rena
l
f
ai
l
ure [48,49]. En
do
-
t
helial or vascular smooth muscle d
y
sfunction is also an
e
ar
l
y mar
k
er o
f
increase
d
car
d
iovascu
l
ar ris
k
in su
b
jects
wit
h
acute coronary syn
d
romes, c
h
ronic coronary an
d
p
eri
p
heral arter
y
disease, h
yp
ertension, and con
g
estive
h
eart
f
ai
l
ure [50–54].
I
ncrease
d
arteria
l
sti
ff
ness an
d
en
d
ot
h
e
l
ia
l
d
ys
f
unction
have been consistentl
y
described in h
yp
ertension, obesit
y
,
an
d
type 2
d
ia
b
etes [55–58]. For instance, our group
h
as
s
h
own t
h
at en
d
ot
h
e
l
ium-
d
epen
d
ent vaso
d
i
l
ation in
d
uce
d
b
y
acet
y
lcholine is im
p
aired in obese, t
yp
e 2 diabetic
p
atients
an
d
in su
b
jects wit
h
g
l
ucose into
l
erance [59]. Important
l
y,
e
n
d
ot
h
e
l
ium-in
d
epen
d
ent vaso
d
i
l
atation to nitroprussi
d
e
is si
g
nicantl
y
im
p
aired in human obesit
y
,
g
lucose into
l
-
e
rance, or
d
ia
b
etes me
ll
itus in comparison wit
h
matc
h
e
d
nono
b
ese contro
l
su
bj
ects. T
h
is

n
d
in
g
in
d
icates t
h
at
t
he insulin resistance s
y
ndrome causes vascular smooth
musc
l
e
d
ys
f
unction [59]. Suc
h
vascu
l
ar
d
ys
f
unction cou
ld
contribute to the progressive increment of arterial stiff
-
f
f
ness in obesit
y
and t
yp
e 2 diabetes. Wei
g
ht loss im
p
roves
e
n
d
ot
h
e
l
ia
l
f
unction an
d
d
ecreases arteria
l
sti
ff
ness [58].
Furt
h
ermore,
b
rac
h
ia
l
arter
y

ow-me
d
iate
d
vaso
d
i
l
ation is
inversel
y
correlated with increased ambulator
y
PP in never-
t
reate
d
h
ypertensive su
b
jects [60]. T
h
ese o
b
servations
corro
b
orate t
h
e conce
p
t t
h
at en
d
ot
h
e
l
ia
l
dy
s
f
unction an
d
arterial stiffness interact mechanisticall
y
, even thou
g
h the
d
irection o
f
t
h
is re
l
ations
h
ip is unc
l
ear (Fig. 2).
A
dd
i
t
i
o
n
al
ev
i
de
n
ce
fo
r
a
n in
te
r
act
i
o
n
betwee
n
e
ndothelial d
y
sfunction and arterial stiffness has been
o
b
serve
d
in
h
yper
h
omocysteinemia, w
h
ic
h
is associate
d
wit
h
increase
d
car
d
iovascu
l
ar ris
k
t
h
roug
h
en
d
ot
h
e
l
ia
l
d
y
sfunction, increased oxidative stress, and athero
g
enic
an
d
t
h
rom
b
osis propensity [61]. In
h
ea
l
t
h
y su
b
jects, ora
l
a
d
ministration o
f
met
h
ionine acute
l
y increases p
l
asma
homoc
y
steine and im
p
airs endothelial function of both
con
d
uit an
d
resistance arteries [62]. Homocysteine-
in
d
uce
d
en
d
ot
h
e
l
ia
l
d
ys
f
unction cou
ld
b
e part
l
y exp
l
aine
d
b
y
an increase of as
y
mmetrical dimeth
y
lar
g
inine, which
d
ecreases NO generation t
h
roug
h
in
h
i
b
ition o
f
NO
synt
h
ase [63,64]. Circu
l
ating asymmetrica
l
d
imet
h
y
l
-
ar
g
inine is inde
p
endentl
y
associated with increased
arteria
l
wave re

ections in su
b
jects un
d
ergoing
d
iagnostic
coronary angiograp
h
y [65]. Important
l
y, met
h
ionine
loadin
g
acutel
y
im
p
airs brachial arter
y
distensibilit
y
and
th
is is strong
l
y corre
l
ate
d
wit
h
d
ecrease
d
en
d
ot
h
e
l
ium-
d
epen
d
ent

ow-me
d
iate
d
d
i
l
atation o
f
t
h
e
b
rac
h
ia
l
artery
[66]. This result su
gg
ests that endothelial d
y
sfunction
increases arteria
l
sti
ff
ness in
h
yper
h
omocysteinemia
.
Pharmacologic Improvement of Arterial
Sti
ff
ness an
d
En
d
ot
h
e
l
ia
l
D
y
s
f
unction
T
h
e
r
e
i
s
substa
n
t
i
a
l
debate
a
r
ou
n
d
t
h
e
m
ec
h
a
ni
s
m
s
o
f
t
h
e
re
d
uction in car
d
iovascu
l
ar events cause
d
b
y anti
h
ypertensive

A
rteria
l
Com
pl
iance an
d
En
d
ot
h
e
l
ia
l
Functio
n
C
orreia an
d
Ha
y
nes 2
73
medications. Some effects a
pp
ear to de
p
end on the de
p
ressor
ef
cacy o
f
me
d
ications, w
h
ereas ot
h
er e
ff
ects mig
h
t
b
e
d
ue
t
o BP-in
d
e
p
en
d
ent
d
irect
ph
armaco
l
o
g
ic actions on vascu
l
ar
biolo
gy
[67]. Im
p
ortantl
y
, the im
p
act of stiffer arteries and
e
n
d
ot
h
e
l
ia
l
d
ys
f
unction on g
l
o
b
a
l
car
d
iovascu
l
ar ris
k
can
b
e
attenuate
d
b
y existing p
h
armaco
l
ogic interventions.
The ASCOT-BPLA (An
g
lo-Scandinavian Cardiac Ou
t
-
comes Tria
l
-B
l
oo
d
Pressure Lowering Arm) i
ll
ustrates t
h
is
issue [68]. T
h
e ASCOT-BPLA ran
d
omize
d
19,257
h
ype
r
-
t
ensive sub
j
ects to two treatment arms: amlodi
p
ine addin
g
p
erin
d
opri
l
(am
l
o
d
ipine-
b
ase
d
regimen) or ateno
l
o
l
a
dd
ing
b
en
d
ro

umet
h
iazi
d
e (ateno
l
o
l
-
b
ase
d
regimen) as nee
d
e
d
to
achieve
p
res
p
ecied brachial arter
y
BP tar
g
ets. The amlo
-
d
ipine-
b
ase
d
regimen prevente
d
car
d
iovascu
l
ar outcomes
more e
ff
ective
l
y t
h
an t
h
e ateno
l
o
l
-
b
ase
d
regimen. However,
t
he better
p
erformance of the amlodi
p
ine-based re
g
imen
cou
ld
not
b
e entire
l
y exp
l
aine
d
b
y
b
etter contro
l
o
f
b
rac
h
ia
l
B
P, usin
g
com
p
arator
d
ata
f
rom ot
h
er stu
d
ies [67]
.
The CAFE (Conduit Arter
y
Function Evaluation)
su
b
stu
d
y (
n
= 2199) o
f
t
h
e ASCOT tria
l
provi
d
e
d
one
e
xp
l
anation
f
or t
h
e
d
i
ff
erence in e
f
cacy
b
etween regimens
[69••], throu
g
h effects on arterial stiffness and central
aortic BP. Even t
h
oug
h
t
h
e
d
epressor e
ff
ect on
b
rac
h
ia
l
systo
l
ic BP was simi
l
ar wit
h
b
ot
h
regimens, t
h
e am
lo
-
di
p
ine-based re
g
imen was si
g
nicantl
y
more effective in
d
ecreasing t
h
e aortic augmentation in
d
ex an
d
centra
l
aor
-
t
ic systo
l
ic,
d
iasto
l
ic, an
d
PP. In a
dd
ition, caroti
d
-
f
emora
l
PWV was measured in a small number of sub
j
ects in one
p
articipating center
b
ut no
d
i
ff
erences
b
etween regimens
h
ave
b
een o
b
serve
d
. Post
h
oc Cox proportiona
l
h
azar
d
s
modelin
g
indicated that central aortic PP correlated with
th
e composite outcome o
f
tota
l
car
d
iovascu
l
ar events or
p
rocedures, and also develo
p
ment of renal d
y
sfunction.
Th
ere
f
ore, t
h
e CAFE stu
d
y suggests t
h
at car
d
iovascu
l
ar
outcomes mig
h
t
b
e more strong
l
y corre
l
ate
d
wit
h
centra
l
p
ressures and arterial stiffness, which are variabl
y
affected
b
y
d
i
ff
erent c
l
asses o
f
anti
h
ypertensive me
d
ications.
S
evera
l
anti
h
ypertensive me
d
ications improve en
do
-
t
helial function. This effect is consistentl
y
re
p
orted with
angiotensin II antagonists [70,71]. It was a
l
so
d
emon
-
strate
d
t
h
at t
h
e
h
ig
hl
y se
l
ective C
1
blocke
r n
eb
i
volol
acts
as an NO donor throu
g
h the activation of endothelial
C
2
-
a
d
renergic receptors [72]. Important
l
y, ne
b
ivo
l
o
l
can
reverse en
d
ot
h
e
l
ia
l
d
ys
f
unction in
h
ypertensive su
b
jects
inde
p
endent of chan
g
es in BP [73]. Moreover, nebivolol
d
ecreases PWV in s
h
eep [72] an
d
increases sma
ll
artery
d
istensi
b
i
l
ity an
d
caroti
d
comp
l
iance in
h
umans [74,75].
T
hese results
p
rovide additional evidence for the interac
-
t
ions
b
etween en
d
ot
h
e
l
ia
l
f
unction an
d
t
h
e mec
h
anica
l
p
ro
p
erties o
f
resistance an
d
con
d
uit arteria
l
vesse
l
s.
Co
n
clus
i
o
n
s
A
rterial stiffness has been mainl
y
correlated with struc
-
t
ura
l
components o
f
t
h
e arteria
l
wa
ll
. However, mounting
e
vi
d
ence in
d
icates t
h
at severa
l
mec
h
anisms t
h
at
dy
nam
i
-
call
y
re
g
ulate vascular tone can also acutel
y
alter arterial
sti
ff
ness. Direct intra-arteria
l
pressure measurements o
f
PWV stron
gly
su
gg
est t
h
at en
d
ot
h
e
l
ium-
d
erive
d
NO an
d
ET-1
p
la
y
an im
p
ortant role in the re
g
ulation of art
e
-
ria
l
sti
ff
ness. Furt
h
ermore, NO mo
d
u
l
ates t
h
e activity
o
f
MMPs an
d
mo
d
i

es t
h
e composition o
f
t
h
e vascu
l
ar
e
xtracellular matrix, whereas ET-1 ma
y
cause vascular
h
ypertrop
h
y t
h
roug
h
as yet unc
l
ear mec
h
anisms. T
h
er
e
-
f
ore, it is not surprising t
h
at increase
d
arteria
l
sti
ff
ness
accom
p
anies endothelial d
y
sfunction of several human
d
iseases, nota
bl
y at
h
erosc
l
erosis an
d
h
ypertension.
Increase
d
arteria
l
sti
ff
ness may contri
b
ute to myocar
-
dial h
yp
ertro
p
h
y
, d
y
sfunction, and ischemia, and thus
car
d
iovascu
l
ar events. T
h
ere
f
ore, c
h
anges in arteria
l
sti
ff
ness may provi
d
e a p
l
ausi
bl
e a
dd
itiona
l
mec
h
anism
b
y
which endothelial d
y
sfunction could contribute to the
comp
l
ications o
f
at
h
erosc
l
erosis, in a
dd
ition to
d
erange
d
v
asomotion,
pl
a
q
ue sta
b
i
l
it
y
, an
d
t
h
rom
b
osis. T
h
ere are
now noninvasive technolo
g
ies for assessin
g
arterial stiff
-
ness t
h
at may provi
d
e
l
ess comp
l
ex an
d
more repro
d
uci
bl
e
in
d
icators o
f
en
d
ot
h
e
l
ia
l
f
unction t
h
an existing measures.
Finall
y
,
p
harmacolo
g
ic mani
p
ulation of endothelial
me
d
iators to re
d
uce arteria
l
sti
ff
ness cou
ld
trans
l
ate into
c
l
inica
ll
y re
l
evant improvements o
f
car
d
iovascu
l
ar ris
k.
A
c
k
now
l
e
dg
ments
T
he authors’ research is su
pp
orted b
y
g
rants from the
Nationa
l
Institutes o
f
Hea
l
t
h
(NHLBI: HL14388; NCRR
G
enera
l
C
l
inica
l
Researc
h
Centers program: RR00059).
Dr. Marcelo Correia is
p
artl
y
su
pp
orted b
y
the State Un
i
-
v
ersity o
f
Rio
d
e Janeiro, Brazi
l.
o
Prostac
y
c
l
in ?
o
MMP
s
o
NO
m
Trophic signal
s
m
Trophic signal
s
m
Endothelins
m Arterial
stiffness
F
igure 2. The arterial stiffness is regulated by the interactions of com
-
p
ounds that modify vascular reactivity and morpholo
g
y. Increased
arterial sti
ff
ness could aggravate endothelial dys
f
unction, whereas
d
ecrease
d
nitric oxi
d
e (NO)
b
ioavai
l
a
b
i
l
ity mig
h
t increase arteria
l
stiffness, in a vicious cycle. MMPs—matrix metalloproteinases
.

2
7
4
E
n
d
ot
h
e
l
ia
l
D
y
s
f
unction
R
eferences and Recommended Readin
g
P
apers o
f
particu
l
ar interest, pu
bl
is
h
e
d
recent
l
y,
h
ave been hi
g
hli
g
hted as:
•
O
f im
p
ortance
••
O
f ma
j
or im
p
ortance
1.
Bl
ac
h
er J, Asmar R, Djane S, et a
l
.:
A
ortic pu
l
se wave
ve
l
ocity as a mar
k
er o
f
car
d
iovascu
l
ar ris
k
in
h
ypertensive
pat
i
ents.
H
ypertension 1999,
33:
1111–111
7.
2.
B
l
ac
h
er
J
, Guerin AP, Pannier B, et a
l
.:
A
r
te
ri
al
calc
i
ca
-
tions, arteria
l
sti
ff
ness, an
d
car
d
iovascu
l
ar ris
k
in en
d
-stage
re
n
al
d
i
sease.
H
ypertension 2001,
38:
938
–
9
42
.
3.
B
l
ac
h
er
J
, Guerin AP, Pannier B, et a
l
.: Impact o
f
aortic
sti
ff
ness on surviva
l
in en
d
-stage rena
l
d
isease.
Circ
u
latio
n
1999,
99:
2
4
3
4–24
39.
4.
Mitchell GF, Izzo JL: Evaluation of arterial stiffness.
In
H
ypertension
P
rimer.
E
dited by Izzo JL, Black HR. Phil
a
-
d
elphia: Lippincott, Williams & Wilkins; 2003:351–355
.
5
.•
•
V
erdecchia P, Angeli F, Taddei S:
A
t the beginning o
f
stiffening: endothelial dysfunction meets “pulsology”.
H
ypertension
2006,
48
:
602
–
608.
T
his editorial briey discusses the implications of endothelium-
dependent vascular responses on arterial stiffness
.
6
. Dart AM, Kin
g
well BA: Pulse
p
ressure—a review of
mechanisms and clinical relevance.
J
Am Coll Cardiol
2001,
3
7
:
9
75–
984.
7. Wilkinson IB, MacCallum H, Hu
pp
eretz PC, et al.:
C
han
g
es in the derived central
p
ressure waveform and
p
ulse
p
ressure in res
p
onse to an
g
iotensin II and noradrenaline in
man.
J
Ph
y
sio
l
2001,
5
30
:
541
–55
0
.
8.
Ni
chols
WW:
Cl
ini
cal
m
easu
r
e
m
e
n
t
of
a
r
te
ri
al
st
i
ff
n
ess
o
b
taine
d
f
rom noninvasive
p
ressure wave
f
orms.
A
m
J
H
yp
ertens 2005
,
18(su
ppl
1):
3S
–1
0S.
9.
V
an Tri
jp
MJ, Bos WJ, van
d
er Sc
h
ouw YT, et a
l
.:
No
n-
invasive
ly
measure
d
structura
l
an
d
f
unctiona
l
arteria
l
c
h
aracteristics an
d
coronar
y
h
eart
d
isease ris
k
in mi
ddl
e
-
ag
e
d
an
d
e
ld
er
ly
men. A
therosclerosis
2
006, 18
7:
1
1
0
–11
5.
1
0.
Ol
iver
JJ
, We
bb
D
J
:
No
nin
vas
i
ve
assess
m
e
n
t
of
a
r
te
ri
al
st
i
ff
-
n
ess
a
n
d
ri
sk
of
athe
r
oscle
r
ot
i
c
eve
n
ts.
Arterioscler
Th
ro
m
b
Vasc
B
iol
2003,
23:
55
4–
566.
1
1
.
B
auersac
h
s
J
, Bou
l
oumie A, Mu
l
sc
h
A, et a
l
.:
Vasod
i
la
-
tor
d
ys
f
unction in age
d
spontaneous
l
y
h
ypertensive rats:
c
h
anges in NO synt
h
ase III an
d
so
l
u
bl
e guany
l
y
l
cyc
l
ase
expression, an
d
in superoxi
d
e anion pro
d
uction.
Cardio
-
vasc
Res
1
998, 3
7
:
77
2–
779.
12
.
Safar M, Chamiot-Clerc P, Dagher G, Renaud JF: P
u
l
se
pressure, endothelium function, and arterial stiffness in
spontaneously hypertensive rats.
H
ypertension
2
001,
38:
1
41
6
–1421
.
13.
Nigam A, Mitchell GF, Lambert J, Tardif JC:
R
elation
b
etween conduit vessel stiffness (assessed by tonometry) and
endothelial function (assessed by ow-mediated dilatation)
in patients with and without coronary heart disease. Am
J
C
ardio
l
2003
,
92:
39
5–
399
.
14.
Ichigi Y, Takano H, Umetani K, et al.:
I
ncreased ambul
a
-
tory pulse pressure is a strong risk factor for coronary
endothelial vasomotor dysfunction.
J
Am Coll Cardio
l
200
5
,
4
5
:
1461
–
1466.
1
5.
C
eravolo R, Maio R, Pu
j
ia A, et al.: Pulse
p
ressure and
endothelial d
y
sfunction in never-treated h
yp
ertensive
p
atients.
J
Am Coll Cardio
l
2003,
41
:
1
75
3
–
1
75
8.
16
.Ramse
y
MW, Goodfellow J, Jones CJ, et al.:
E
ndothelial
control of arterial distensibilit
y
is im
p
aired in chronic heart
failure. Circulation
199
5
,
92
:
3212
–
3219.
1
7. C
h
eun
g
YF, C
h
an GC, Ha SY:
A
rteria
l
sti
ff
ness an
d
en
d
o
-
t
h
e
l
ia
l
f
unction in
p
atients wit
h
b
eta-t
h
a
l
assemia ma
j
or.
C
ircu
l
ation 2002
,
106:
2
561–2566
.
18.
R
avi
k
umar R, Dee
p
a R, S
h
ant
h
irani C, Mo
h
an V:
Com
-
p
arison o
f
caroti
d
intima-me
d
ia t
h
ic
k
ness, arteria
l
sti
ff
ness,
a
n
d
b
rac
h
ia
l
arter
y

ow me
d
iate
d
d
i
l
atation in
d
ia
b
etic an
d
non
d
ia
b
etic su
bj
ects (T
h
e C
h
ennai Ur
b
an Po
p
u
l
ation Stu
dy
[
CU
P
S
-
9
]
)
. Am
J
Car
d
io
l
2
002,
90:
70
2–
707.
1
9.•
•
McEnier
y
CM, Wa
ll
ace S, Mac
k
enzie IS, et a
l
.: En
d
ot
h
e
l
ia
l
f
unction is associate
d
wit
h
p
u
l
se
p
ressure,
p
u
l
se wave
v
e
l
ocit
y
, an
d
au
g
mentation in
d
ex in
h
ea
l
t
hy
h
umans.
H
yp
ertension 2006
,
4
8:
6
02–608
.
Ori
g
ina
l
stu
dy
s
h
owin
g
t
h
e corre
l
ation
b
etween en
d
ot
h
e
l
ia
l
f
un
c
-
t
ion an
d
var
y
in
g
d
e
g
rees o
f
arteria
l
sti
ff
ness in
h
ea
l
t
hy
h
umans.
2
0.
•
•
Sc
h
mitt M, Avo
l
io A,
Q
asem A, et a
l
.:
B
asa
l
NO
l
oca
lly
mo
d
u
l
ates
h
uman i
l
iac arter
y
f
unction in vivo.
Hyp
erte
n
-
sio
n 2005, 4
6:
22
7
–2
3
1
.
Ori
g
ina
l
stu
dy
s
h
owin
g
t
h
at NO anta
g
onism is associate
d
wit
h
in
c
r
eased
P
WV
in
hu
m
a
n
s.
21
.
P
eng X, Ha
ld
ar S, Des
h
pan
d
e S, et a
l
.:
Wall
st
i
ff
n
ess
suppresses A
k
t/eNOS an
d
cytoprotection in pu
l
se-per
f
use
d
e
n
dothel
i
u
m
.
H
ypertension
2
003, 41
:
378
–
38
1
.
22
.
V
an
d
er Leyen HE, Gi
bb
ons GH, Moris
h
ita R, et a
l
.:
Ge
n
e
t
h
erapy in
h
i
b
iting neointima
l
vascu
l
ar
l
esion: in vivo
trans
f
er o
f
en
d
ot
h
e
l
ia
l
ce
ll
nitric oxi
d
e synt
h
ase gene.
Proc
N
atl
A
cad
Sci
U
S
A
1
995,
9
2
:
1
1
37
–1141
.
2
3.
Mooradian DL, Hutsell TC, Keefer LK:
N
itric oxide
(
NO
)
do
n
o
r m
o
l
ecu
l
es:
e
ff
ect
o
f
NO
r
e
l
ease
r
ate
o
n
vascu
l
a
r
smooth muscle cell proliferation in vitro. J Cardiovasc
Ph
ar
m
acol
1995, 2
5:
67
4–
678.
24
. Janssens S, Flaherty D, Nong ZX, et al.: Human endothelial
cell nitric oxide synthase gene transfer inhibits vascular
smooth muscle cell proliferation and neointima formation
a
fter balloon injury in rats. Circulation
1998
,
9
7:
12
7
4
–
1281
.
2
5. Tanner FC
,
Meier P
,
Greutert H
,
et al.:
N
itric oxide
modulates expression of cell cycle regulatory proteins: a
cytostatic strategy for inhibition of human vascular smooth
muscle cell proliferation.
C
irculation
2000,
101
:
1982
–
1989.
26.
S
ato J, Nair K, Hiddin
g
a J, et al.: eNOS
g
ene transfer to
v
ascular smooth muscle cells inhibits cell
p
roliferation via
up
re
g
ulation of
p
27 and
p
21 and not a
p
o
p
tosis.
C
ardiovasc
R
es
2000,
4
7
:
69
7–7
06.
2
7.•
•
Zieman SJ, Melenovsk
y
V, Kass DA: Mechanisms,
p
atho
-
p
h
y
siolo
gy
, and thera
py
of arterial stiffness. Arterioscle
r
Throm
b
Vasc Biol
200
5
,
2
5
:
932
–
943
.
Com
p
rehensive review of structural as
p
ects of arterial stiffness.
28.
T
ronc F
,
Ma
ll
at Z
,
Le
h
oux S
,
et a
l
.: Ro
l
e o
f
matrix meta
ll
o
p
r
o
-
teinases in
bl
oo
d

ow-in
d
uce
d
arteria
l
en
l
ar
g
ement: interaction
wit
h
NO. Arterioscler Thromb Vasc Biol
2
000
,
20:E120–126.
2
9.•
Dumont O, Lou
f
rani L, Henrion D: Ke
y
ro
l
e o
f
t
h
e
N
O-
p
at
h
wa
y
an
d
matrix meta
ll
o
p
rotease-9 in
h
i
gh
bl
oo
d

ow-in
d
uce
d
remo
d
e
l
in
g
o
f
rat resistance arteries. A
rterio
-
scler
Th
ro
m
b
Vasc
B
iol
2
007, 2
7:
3
1
7
–
3
24
.
Ori
g
ina
l
stu
dy
d
emonstratin
g
t
h
e mo
d
u
l
ation o
f
MMP activit
y
by
NO
.
30.•
C
h
ew DK, Conte MS, K
h
a
l
i
l
RA:
M
atrix meta
ll
opr
o
-
teinase-speci

c in
h
i
b
ition o
f
Ca2+ entry mec
h
anisms o
f
vascula
r
co
n
t
r
act
i
o
n
.
J Vasc Sur
g
2
004, 4
0:
1
00
1–1
0
1
0.
Origina
l
stu
d
y
d
emonstrating e
ff
ects o
f
MMPs on vascu
l
ar
c
ontracti
l
ity
.
3
1
.
R
a
ff
etto
J
D, Ross RL, K
h
a
l
i
l
RA:
M
atrix meta
ll
oproteinase
2-in
d
uce
d
venous
d
i
l
ation via
h
yperpo
l
arization an
d
activ
a
-
t
i
o
n
of
K+
cha
nn
els:
R
eleva
n
ce
to
va
ri
cose
ve
in
fo
rm
at
i
o
n
.
J
V
asc Surg 2007,
45:
373
–
380.
3
2
.
P
ar
k
ington HC, Co
l
eman HA, Tare M:
P
rostacyc
l
in an
d
en
d
ot
h
e
l
ium-
d
epen
d
ent
h
yperpo
l
arization. P
har
m
acol
R
es
2004, 4
9:
509
–
5
14
.
33
.
J
oannides R, Haefeli W, Linder L, et al.: Nitric oxide
is responsible for ow-dependent dilatation of human
peripheral conduit arteries in vivo. Circulation
199
5,
91
:
1314
–
1319
.
34.
Nakayama T, Hironaga T, Ishima H, et al.: The prostacyclin
a
nalogue beraprost sodium prevents development of arterial
stiffness in elderly patients with cerebral infarction.
P
rost
a
-
g
landins Leukot Essent Fatty Acids
2004,
70
:
491
–
494
3
5. Wu Y, Huan
g
A, Sun D, et al.: Gender-s
p
ecic com
p
ens
a
-
tion for the lack of NO in the mediation of ow-induced
a
rteriolar dilation. Am
J
Ph
y
siol Heart Circ Ph
y
siol
2001,
280:
H
24
5
6
–H
2461
.
36
. Sun D, Huan
g
A, Smith CJ, et al.:
E
nhanced release of
p
ros-
ta
g
landins contributes to ow-induced arteriolar dilation in
eNOS knockout mice.
C
irc Res
1999,
8
5:
288
–
293.

A
rteria
l
Com
pl
iance an
d
En
d
ot
h
e
l
ia
l
Functio
n
C
orreia an
d
Ha
y
nes 2
75
3
7.
B
r
y
an RM Jr, You J, Go
ld
in
g
EM, Marre
ll
i SP: En
d
ot
he
-
l
ium-
d
erive
d
hyp
er
p
o
l
arizin
g
f
actor: a cousin to nitric oxi
d
e
a
n
d
p
rostac
y
c
l
in.
A
nest
h
esio
l
o
gy
2005
,
1
02:
1
261–1277
.
38.
F
l
emin
g
I, Busse R:
E
n
d
ot
h
e
l
ium-
d
erive
d
e
p
ox
y
eicosatr
i
-
e
n
o
i
c
ac
i
ds
a
n
d
vascula
r
fu
n
ct
i
o
n
.
H
yp
ertension 2006,
4
7:
6
2
9
–
633.
39.
B
e
ll
ien
J
, Iaco
b
M, Gutierrez L, et a
l
.:
C
r
uc
i
al
r
ole
of
NO an
d
en
d
ot
h
e
l
ium-
d
erive
d
h
yperpo
l
arizing
f
actor in
h
uman sustaine
d
con
d
uit artery

ow-me
d
iate
d
d
i
l
atation.
Hypertension 2006,
48:
1
088
–1
09
4
.
4
0.
T
a
dd
ei S, Versari D, Cipriano A, et a
l
.: I
de
n
t
i
cat
i
o
n
of
a
cytoc
h
rome P450 2C9-
d
erive
d
en
d
ot
h
e
l
ium-
d
erive
d
h
yperpo
l
arizing
f
actor in essentia
l
h
ypertensive patients.
J
Am
Coll
Cardiol
2006,
48:
508
–
5
1
5.
41
.
A
gapitov
A
V, Haynes WG:
Ro
l
e
o
f
e
n
dot
h
e
lin in
ca
r
d
i
ovascu
l
a
r
d
i
sease.
J Renin Angiotensin Aldosterone Syst 2002,
3:
1
–1
5.
42
.
M
cEniery CM, Qasem A, Schmitt M, et al.:
E
ndothelin-1
r
egulates arterial pulse wave velocity in vivo. J Am Coll
C
ardio
l
2003
,
42:
19
75–
1981.
43.
H
eintz B
,
Dorr R
,
Gillessen T
,
et al.: Do arterial endothelin
1
levels affect local arterial stiffness?
A
m Heart
J
1993,
126
:
98
7–
989.
44
. Takahashi M: The role of endothelin-1 in vascular remode
l
-
in
g
in vivo.
C
ardiovasc Res
2006,
71
:
4
–5
.
4
5. Benetos A
,
Safar M
,
Rudnichi A
,
et al.: Pulse
p
ressure: a
p
redictor of lon
g
-term cardiovascular mortalit
y
in a French
male
p
o
p
ulation.
Hyp
ertension
199
7
,
30
:
1410
–
140
5
.
4
6. Benetos A
,
Ru
d
nic
h
i A
,
Sa
f
ar M
,
Guize L:
P
u
l
se
p
ressure
a
n
d
car
d
iovascu
l
ar morta
l
it
y
in normotensive an
d
hyp
e
r
-
tensive su
bj
ects.
Hyp
ertension 1998
,
3
2:560–564.
4
7.
Fran
kl
in SS, K
h
an SA, Won
g
ND, et a
l
.: Is
p
u
l
se
p
ressure
u
se
f
u
l
in
p
re
d
ictin
g
ris
k
f
or coronar
y
h
eart
d
isease? T
h
e
Framin
gh
am Heart stu
dy
.
Circ
u
latio
n 1999,
100:
35
4–
360.
48.
Boutouyrie P, Tropeano AI, Asmar R, et a
l
.:
Ao
r
t
i
c
st
i
ff
n
ess
is an in
d
epen
d
ent pre
d
ictor o
f
primary coronary events in
h
ypertensive patients: a
l
ongitu
d
ina
l
stu
d
y.
H
ypertension
2002,
39:
10
–1
5.
49.
B
l
ac
h
er
J
, Sa
f
ar ME, Guerin AP, et a
l
.:
A
ortic pu
l
se wave
ve
l
ocity in
d
ex an
d
morta
l
ity in en
d
-stage rena
l
d
isease.
Ki
d
ney Int
2
003,
63:
1
85
2–1
860.
50.
Fichtlscherer S, Breuer S, Zeiher AM:
P
rognostic value of
systemic endothelial dysfunction in patients with acute
coronary syndromes: further evidence for the existence of the
“vulnerable” patient.
Circ
u
latio
n 2004,
1
1
0:
1
9
2
6
–1
93
2
.
5
1
. Perticone F, Ceravolo R, Pujia A, et al.: Prognostic signi

-
cance of endothelial dysfunction in hypertensive patients.
C
irculation
2001
,
104
:
191
–
196
.
5
2.
Brevetti G
,
Silvestro A
,
Schiano V
,
Chiariello M: End
o
-
thelial dysfunction and cardiovascular risk prediction in
peripheral arterial disease: additive value of ow-mediated
dilation to ankle-brachial pressure index. Circulation
2003,
108
:
2093
–
2098.
5
3
. Heitzer T, Schlinzi
g
T, Krohn K, et al.:
E
ndothelial d
y
sfun
c
-
tion
,
oxidative stress
,
and risk of cardiovascular events in
p
atients with coronar
y
arter
y
disease.
C
irculation
2001,
104:
26
7
3
–
26
7
8
.
5
4.
Heitzer T
,
Baldus S
,
von Kodolitsch Y
,
et al.:
Sy
stemic
endothelial d
y
sfunction as an earl
y
p
redictor of adverse
outcome in heart failure. Arterioscler Throm
b
Vasc Bio
l
200
5
,
2
5:
11
7
4
–
11
7
9
.
55.
Wi
ll
iams SB, Cusco JA, Ro
ddy
MA, et a
l
.: Im
p
aire
d
nitric
oxi
d
e-me
d
iate
d
vaso
d
i
l
ation in
p
atients wit
h
non-insu
l
in-
d
e
p
en
d
ent
d
ia
b
etes me
ll
itus.
J
Am Co
ll
Car
d
io
l
1
996
,
2
7:
567–574.
56.
Hi
g
as
h
i Y, Sasa
k
i S, Na
k
a
g
awa K, et a
l
.: E
ff
ect o
f
o
b
esit
y
on en
d
ot
h
e
l
ium-
d
e
p
en
d
ent, nitric oxi
d
e-me
d
iate
d
vaso
d
i
l
a
-
tion in normotensive in
d
ivi
d
ua
l
s an
d
p
atients wit
h
essentia
l
hyp
ertension.
A
m
J
H
yp
ertens
2
001,
1
4
:
1
038
–1
0
4
5.
57.
Te
d
esco MA, Nata
l
e F, Di Sa
l
vo G, et a
l
.: E
ffects
of
coe
xi
st
-
ing
h
ypertension an
d
type II
d
ia
b
etes me
ll
itus on arteria
l
st
i
ff
n
ess.
J Hum Hypertens
2
004, 1
8:
4
69
–4
73.
5
8
.
W
i
ld
man RP
,
Far
h
at GN
,
Pate
l
AS
,
et a
l
.: Wei
gh
t c
h
an
g
e is
a
ssociate
d
wit
h
c
h
an
g
e in arteria
l
sti
ff
ness amon
g
h
ea
l
t
hy
y
oun
g
a
d
u
l
ts. H
yp
ertension 2005
,
45:187–192
.
59.
Sivitz WI, Wa
y
son SM, Ba
yl
ess ML, et a
l
.: O
b
esit
y
im
p
airs
v
ascu
l
ar re
l
axation in
h
uman su
bj
ects:
hyp
er
gly
cemia
exa
gg
erates a
d
rener
g
ic vasoconstriction.
J
Diabetes
C
om
pl
ications
2
007, In
p
ress.
60.
Ceravo
l
o R, Maio R, Pujia A, et a
l
.: Pu
l
se pressure an
d
en
d
ot
h
e
l
ia
l
d
ys
f
unction in never-treate
d
h
ypertensive
pat
i
ents.
J
Am Co
ll
Car
d
io
l
2003,
4
1
:
1753
–1
758.
6
1
.
G
ut
h
i
k
on
d
a S, Haynes WG: Homocysteine: ro
l
e an
d
imp
l
ications in at
h
erosc
l
erosis.
C
urr At
h
erosc
l
er Rep 2006,
8:
1
00
–1
06.
6
2
.
K
anani PM, Sinkey CA, Browning RL, et al.:
Ro
l
e
of
oxidant stress in endothelial dysfunction produced by
experimental hyperhomocyst(e)inemia in humans.
Circ
u
la
-
tio
n
1
999, 1
00:
1
1
6
1–11
68.
63.
B
oger RH, Lentz SR, Bode-Boger SM, et al.:
E
levation o
f
a
symmetrical dimethylarginine may mediate endothelial
dysfunction during experimental hyperhomocyst(e)inaemia
in humans. Clin Sci (Lond)
2001
,
100
:
161
–
16
7
.
64.
Sy
dow K, Horni
g
B, Arakawa N, et al.:
E
ndothelial
d
y
sfunction in
p
atients with
p
eri
p
heral arterial disease and
chronic hyperhomocysteinemia: potential role of ADMA.
V
asc Me
d
2004,
9:
93
–
101
.
6
5
.
W
eber T, Maas R, Auer J, et al.:
A
rterial wave reections
a
nd determinants of endothelial function a h
yp
othesis
b
ased on
p
eri
p
heral mode of action.
A
m
J
H
yp
ertens
200
7
,
20
:
2
5
6
–
262
.
66
.
A
l-Shaer MH, Ra
g
huveer G, Brownin
g
R, et al.: Effect o
f
h
yp
erhomoc
y
steinemia induced b
y
methionine administra-
tion on ow-mediated dilatation of the brachial arter
y
in
health
y
sub
j
ects. Am
J
Cardio
l
200
5
,
9
5
:
428
–
430
.
6
7. Pou
l
ter NR
,
We
d
e
l
H
,
Da
hl
o
f
B
,
et a
l
.: Ro
l
e o
f
bl
oo
d
p
ressure an
d
ot
h
er varia
bl
es in t
h
e
d
i
ff
erentia
l
car
d
iova
s
-
cu
l
ar event rates note
d
in t
h
e An
gl
o-Scan
d
inavian Car
d
iac
O
utcomes Tria
l
-B
l
oo
d
Pressure Lowerin
g
Arm (ASCOT-
BPL
A
).
L
ancet 2005
,
366
:
907–913
.
68.
Da
hl
o
f
B, Sever PS, Pou
l
ter NR, et a
l
.: Pr
eve
n
t
i
o
n
of
car
d
iovascu
l
ar events wit
h
an anti
hyp
ertensive re
g
imen o
f
a
m
l
o
d
i
p
ine a
dd
in
g
p
erin
d
o
p
ri
l
as re
q
uire
d
versus ateno
l
o
l
add
in
g
b
en
d
ro

umet
h
iazi
d
e as re
q
uire
d
, in t
h
e An
gl
o-Sca
n
-
d
inavian Car
d
iac Outcomes Tria
l
-B
l
oo
d
Pressure Lowerin
g
Arm (ASCOT-BPLA): a mu
l
ticentre ran
d
omize
d
contro
ll
e
d
t
ri
al.
L
a
n
cet
2005,
366:
895
–
906.
69.
•• Wi
ll
iams B, Lacy PS, T
h
om SM, et a
l
.:
D
i
ff
erentia
l
impact
o
f
bl
oo
d
pressure-
l
owering
d
rugs on centra
l
aortic pressure
a
n
d
c
l
inica
l
outcomes: principa
l
resu
l
ts o
f
t
h
e Con
d
uit
Artery Function Eva
l
uation (CAFE) stu
d
y.
Circ
u
latio
n
2006,
1
1
3:
121
3
–122
5.
Origina
l
ran
d
omize
d
c
l
inica
l
tria
l
s
h
owing t
h
e
d
i
ff
erentia
l
e
ff
ects
o
f
d
iverse anti
h
ypertensive p
h
armaco
l
ogic regimens on centra
l
BPs
a
n
d
in
d
i
ces
of
a
r
te
ri
al
st
i
ff
n
ess.
70.
Kl
ing
b
ei
l
AU, Jo
h
n S, Sc
h
nei
d
er MP, et a
l
.:
Effect
of
AT1
r
eceptor
bl
oc
k
a
d
e on en
d
ot
h
e
l
ia
l
f
unction in essentia
l
h
ypertension.
A
m J Hypertens 2003, 1
6:
12
3
–12
8.
7
1
.
Th
ui
ll
ez C, Ric
h
ar
d
V: Targeting en
d
ot
h
e
l
ia
l
d
ys
f
unction in
h
ypertensive su
b
jects.
J
H
um
H
ypertens
2
005, 19(supp
l
1):
S
21–
S
2
5.
7
2.
McEniery CM, Schmitt M, Qasem A, et al.: Nebivolol
increases arterial distensibility in vivo.
H
ypertension
2004
,
44:
30
5–
310.
7
3
.
T
zemos N
,
Lim PO
,
MacDonald TM: Nebivolol reverses
endothelial dysfunction in essential hypertension: a ra
n
-
domized, double-blind, crossover study. Circulation
2001,
104:
5
11
–5
14
.
7
4
. Zanchetti A: Clinical
p
harmacod
y
namics of nebivolol: new
evidence of nitric oxide-mediated vasodilatin
g
activit
y
and
p
eculiar haemod
y
namic
p
ro
p
erties in h
yp
ertensive
p
atients.
Blood Press Su
ppl
2004,
1
:
1
7–
32.
75
.
V
an Merode T
,
van Bortel LM
,
Smeets FA
,
et al.: Vera
p
amil
a
nd nebivolol im
p
rove carotid arter
y
distensibilit
y
in h
yp
er
-
tensive
p
atients.
J
H
yp
ertens Su
pp
l
1989,
7:
S
262–
S
263.