Redox signaling in hypertension
Tamara M. Paravicini, Rhian M. Touyz*
Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, K1H 8M5, Ontario, Canada
Received 10 January 2006; received in revised form 2 May 2006; accepted 3 May 2006
Available online 9 May 2006
Time for primary review 21 days
Diseases such as hypertension, atherosclerosis and diabetes are associated with vascular functional and structural changes including
endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in
vascular smooth muscle cell (VSMC) growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many stimuli influence
cellular changes, including mechanical forces, such as shear stress, and vasoactive agents, of which angiotensin II (Ang II) appears to
be amongst the most important. Ang II mediates many of its pleiotropic vascular effects through NAD(P)H oxidase-derived reactive
oxygen species (ROS). Mechanical forces, comprising both unidirectional laminar and oscillatory shear, are increasingly being
recognized as important inducers of vascular NO and ROS generation. In general, laminar flow is associated with upregulation of
eNOS and NO production and increased expression of antioxidants glutathione peroxidase and superoxide dismutase, thereby promoting
a healthy vascular wall and protecting against oxidative vascular injury. On the other hand, oscillatory shear is linked to increased
ROS production with consequent oxidative damage, as occurs in hypertension. ROS function as important intracellular and intercellular
second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine
kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to
VSMC growth and migration, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS
increase intracellular free Ca2+concentration, a major determinant of vascular reactivity. ROS influence signaling molecules by
altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, low concentrations of
intracellular ROS play an important role in normal redox signaling involved in maintaining vascular function and integrity. Under
pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review describes
some of the redox-sensitive signaling pathways that are involved in the functional and structural vascular changes associated with
D 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Superoxide; Signal transduction; Angiotensin II; Kinases; Vascular smooth muscle cells; Blood pressure; Vascular remodeling; Inflammation
One of the key characteristics of hypertension is
increased peripheral resistance, due largely to a reduced
lumen diameter of resistance vessels . Since resistance is
inversely proportional to the fourth power of the radius, a
small change in diameter can significantly impact on
vascular resistance. The small arteries and arterioles that
determine peripheral resistance undergo both structural and
functional changes in hypertension . Examples of these
changes include increased reactivity to contractile agents,
impaired endothelial function, vascular smooth muscle
growth, extracellular matrix deposition and vascular inflam-
Over the past decade, the role of reactive oxygen species
(ROS) in the cardiovascular system has been the subject of
much research interest. The ROS Ffamily_ encompasses
various molecules, which have wide-ranging and divergent
effects on cellular function. Within the cardiovascular
system, the major effects of ROS include regulation of cell
0008-6363/$ - see front matter D 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Tel.: +1 613 562 5800x8241; fax: +1 613 562
E-mail address: email@example.com (R.M. Touyz).
Cardiovascular Research 71 (2006) 247 – 258
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growth and differentiation, modulation of extracellular
matrix production and breakdown, inactivation of nitric
oxide (NO) and stimulation of many kinases . Impor-
tantly, many of these effects are associated with pathological
changes observed in hypertension.
The term Foxidative stress_ describes conditions involv-
ing chronically elevated ROS levels and is associated with
cardiovascular disease. Patients with hypertension demon-
strate increased levels of oxidative stress byproducts
together with decreased activity of endogenous antioxidant
enzymes in blood and mononuclear cells . These patients
also have indications of increased oxidative DNA damage
when compared to normotensive individuals . Direct
measurements of ROS production from stimulated mono-
nuclear cells showed that cells isolated from hypertensive
patients had higher levels of O2
stimulation with phorbol myristate acetate, angiotensin II
(Ang II) or endothelin-1 when compared to normotensive
subjects . Similarly, patients with renovascular hyperten-
sion (who have elevated plasma renin activity and Ang II
levels) demonstrate increased oxidative stress together with
impaired endothelium-dependent vasodilatation . Vascu-
lar ROS production is also elevated in a range of different
experimental models of hypertension, including Ang II-
induced [8,9], mineralocorticoid  and renovascular
hypertension [11,12]. Thus, there is compelling evidence
to suggest a role for ROS in the pathogenesis of
Although all ROS are derived from the reduction of
molecular oxygen, the different chemical properties of
individual ROS have important implications for their role
in cellular signaling. Both O2
short biological half-lives—the OH&radical is particularly
reactive, and thus unlikely to mediate effects distant from
where it is produced. The charge on the superoxide anion
makes it unable to cross cellular membranes except
possibly through ion channels. In contrast, H2O2 has a
longer biological life span than O2
to diffuse across lipid bilayers. These distinct properties
mean that different species of ROS are capable of
activating different signaling pathways, which may then
lead to divergent (and potentially opposing) consequences.
For example, increased O2
to inactivate the vasodilator, leading to endothelial
dysfunction and vasoconstriction characteristic of many
vascular diseases, including hypertension . H2O2,
however, has been shown to act as a vasodilator in a
number of vascular beds, including cerebral, coronary and
mesenteric arteries [14–16]. Thus, broadly attributing
effects to Foxidative stress_ without examining the
individual ROS-modulated signaling pathways involved
may be a simplistic representation of what is actually
occurring in vivo. The present review describes some of
the redox-sensitive signaling pathways that are involved in
the functional and structural vascular changes associated
&?and OH&have relatively
&?and OH&and is able
&?levels have long been known
2. Production and metabolism of ROS
ROS are produced by all vascular cell types, including
endothelial, smooth muscle and adventitial cells, and can be
formed by numerous enzymes. The most relevant sources of
ROS with respect to vascular disease and hypertension
appear to be xanthine oxidase, uncoupled endothelial NO
synthase and NAD(P)H oxidase.
Xanthine oxidase is a metalloenzyme that catalyses the
oxidation of hypoxanthine and xanthine to form O2
known to be present in the vascular endothelium. Although
xanthine oxidase-derived O2
the context of ischemia–reperfusion injury and heart failure,
there is also some evidence to suggest involvement in the
endothelial dysfunction seen in hypertension. Spontaneous-
ly hypertensive rats (SHR) demonstrate elevated levels of
xanthine oxidase activity in the mesenteric microcirculation,
and this is associated with increased arteriolar tone .
Endothelial dysfunction in transgenic rats with overexpres-
sion of renin and angiotensinogen has also been associated
with increased xanthine oxidase activity . In addition to
effects on the vasculature, xanthine oxidase may play a role
in end-organ damage in hypertension. Both SHR and Dahl
salt-sensitive rats exhibit increased xanthine oxidase activity
in the kidney. In the SHR, long-term inhibition of xanthine
oxidase with allopurinol reduced renal xanthine oxidase
activity without lowering blood pressure, indicating that the
increased renal ROS production was a consequence of
hypertension rather than a contributing factor . The
finding that allopurinol can improve cardiac and renal
hypertrophy in SHR whilst having a minimal impact on
blood pressure  supports a role for xanthine oxidase in
hypertensive end-organ damage rather than in the develop-
ment of hypertension per se.
Nitric oxide synthase (NOS) can also contribute to ROS
production, as all three NOS isoforms have been shown to
be susceptible to the Funcoupling_ that leads to the formation
endothelial NOS, this process can be triggered in vitro
through the absence of the co-factors l-arginine and
tetrahydrobiopterin . Importantly, uncoupling of endo-
thelial NOS has been demonstrated in mice with DOCA-
salt-induced hypertension . The critical step in this
uncoupling seems to be oxidation of tetrahydrobiopterin by
ONOO?, reducing the bioavailability of this critical cofactor
[23,24]. Treatment with tetrahydrobiopterin improves blood
pressure in both DOCA-salt hypertension and SHR [23,25].
Over the last decade, many studies have shown that the
major source of ROS in the vascular wall is nonphagocytic
NAD(P)H oxidase, which utilises NADH/NADPH as the
electron donor to reduce molecular oxygen and produce
both cytosolic (p47phox, p67phox or homologues) and
membrane bound (gp91phox/Nox1/Nox4 and p22phox)
subunits to form a functional enzyme complex. In the
vasculature the NAD(P)H oxidase complex is at least partly
&?, and is
&?has been primarily studied in
&?(rather than NO) under certain conditions . For
&?. Activation of this enzyme requires the assembly of
T.M. Paravicini, R.M. Touyz / Cardiovascular Research 71 (2006) 247–258
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