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Carvalho et al., J Hypertens 2012, 1:3

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Brain Angiotensin-II-derived Reactive Oxygen Species: Implications for

High Blood Pressure
Alynne S. Carvalho, Drielle D. Guimaraes, Bruna P. V. Dantas, Juliana N. Carreiro, Leonidas G. Mendes-Junior, Maria S. Frana-Silva,
Matheus M.O. Monteiro, Naiane F.B. Alves, Sunia K.P. Porpino,Thyago M. Queiroz and Valdir A. Braga*
Biotechnology Center, Federal University of Paraiba, Joo Pessoa, PB, Brazil

Abstract
Hypertension and its relation to free radicals have been matter of continuous research worldwide. This review is
based on the premise that some forms of neurogenic hypertension is, in part, caused by the formation of AngiotensinII (Ang II)-derived reactive oxygen species within the brain, especially in areas along the Subfornical OrganParaventricular Nucleus of the Hypothalamus-Rostral Ventrolateral Medulla pathway (SFO-PVN-RVLM pathway). Here
we will discuss the recent contribution of our laboratory and others regarding the mechanisms by which neurons in the
Rostral Ventrolateral Medulla (RVLM) are activated by Ang II, how they communicate with the SFO and PVN and more
importantly, how Ang II-derived Reactive Oxygen Species (ROS) participate along the SFO-PVN-RVLM pathway in the
pathogenesis of neurogenic hypertension.

Keywords: Superoxide; Sympathetic; Angiotensin; Subfornical

organ; Rostral ventrolateral medulla

Introduction
The mechanisms underlying neurogenic hypertension have been
matter of continuous research worldwide. This review focus on the
hypothesis that neurogenic hypertension is, in part, caused by the
formation of Angiotensin-II (Ang II)-derived reactive oxygen species
in key cardiovascular nuclei, especially in the Rostral Ventrolateral
Medulla (RVLM).
Ang II is the major effector of the ReninAngiotensinAldosterone
System (RAAS). This system consists mainly of a 2-step enzymatic
cascade catalyzed by renin and Angiotensin-Converting Enzyme
(ACE), generating Ang II [1], the effect of Ang II is mediated by Ang
II receptors. Two isoforms of Ang II receptor have been identified:
type 1 receptor (AT1R) and type 2 receptor (AT2R). In general, it is
accepted that cardiovascular effects of Ang II such as vasoconstriction,
regulation of fluid and drinking behavior are ascribed to AT1R.
Besides, AT1R is involved in the progression of cardiovascular diseases
including hypertension, atherosclerosis, cardiac hypertrophy and heart
failure [2,3].
An additional component of the RAAS family, angiotensinconverting enzyme2 (ACE2) cleaves Ang I and Ang II into Ang 1-9
and Ang 1-7, respectively [4]. Studies show that ACE2 promotes
beneficial effects, such as important in vasodilatation, natriuresis and
to inhibit heart failure. These effects seems to be related with inhibition
of oxidative stress, since ACE2 deficiency leads to an Ang II-mediated
activation of the NADPH oxidase system and exacerbated oxidative
stress leading to hypertension [4,5]. Abundant evidence now points to
oxidative stress as a key mechanism in Ang II-dependent neurogenic
hypertension [6,7]. Furthermore, it has become evident that reactive
oxygen species are important in the increase in blood pressure elicited
by Ang II administered peripherally or directly in the Central Nervous
System (CNS). However, considering that Ang II is composed by eight
amino acids, which makes it incapable of crossing the Blood Brain
Barrier (BBB), the mechanisms underlying how circulating Ang II
acts within the brain to eventually modulate sympathetic activity and
induce hypertension remain unknown. The most accepted hypothesis
is that angiotensin II, as any other circulating lipophobic substance,
acts on neurons in specialized regions of the brain known as the
J Hypertens
ISSN: 2167-1095 JHOA an open access journal

Circumventricular Organs (CVOs), which partially lack the normal

BBB, in order to alter the function of other brain regions protected by
this important barrier that filters what enters the CNS. As a result,
activation of the CVOs triggers the local production of Ang II in
brain areas protected by BBB, mainly the RVLM, which in turn alters
sympathetic drive. Here we will discuss the recent advances regarding
the mechanisms by which neurons in the RVLM are activated by Ang
II/ROS and how Ang II-derived reactive oxygen species participate
along the SFO-PVN-RVLM pathway in the context of neurogenic
hypertension.

Reactive Oxygen Species in the Brain

The pathways for production of reactive oxygen species in
mammalian cells have been revised elsewhere [8]. The first evidence
that Ang II activates NADPH oxidase in vascular smooth muscle
cells to produce ROS was presented by Griendling and colleagues [9].
More recently, accumulating evidence from our laboratory and others
suggest that, like vascular cells, neurons also require ROS to carry out
crucial functions related to central control of blood pressure [10-15].
There is compelling evidence that superoxide anion is necessary to
elicit the vasopressor, bradycardic, and dipsogenic responses produced
by intracerebroventricular (ICV) administration of Ang II in conscious
mice [16]. It has also been shown that Ang II causes robust increases
in superoxide production in cultured SFO neurons. In addition,
adenoviral-mediated delivery of cytoplasmically targeted superoxide
dismutase (SOD) selectively to the SFO abolishes the cardiovascular
and dipsogenic actions of Ang II in normotensive mice and prevents

*Corresponding author: Valdir Andrade Braga, PhD, Biotechnology Center,

Federal University of Paraiba, Caixa Postal 5009, 58.051-970, Joo Pessoa, PB,
Brazil, Tel: (55) 83 3216 7511; E-mail: valdir@[Link]
ReceivedMay 22, 2012; Accepted July 24, 2012; Published July 26, 2012
Citation: Carvalho AS, Guimaraes DD, Dantas BPV, Carreiro JN, MendesJunior LG, et al. (2012) Brain Angiotensin-II-derived Reactive Oxygen Species:
Implications for High Blood Pressure. J Hypertens 1:107. doi:10.4172/21671095.1000107
Copyright: 2012 Carvalho AS, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.

Volume 1 Issue 3 1000107

Citation: Carvalho AS, Guimaraes DD, Dantas BPV, Carreiro JN, Mendes-Junior LG, et al. (2012) Brain Angiotensin-II-derived Reactive Oxygen
Species: Implications for High Blood Pressure. J Hypertens 1:107. doi:10.4172/2167-1095.1000107

Page 2 of 3
the hypertension in chronic peripheral Ang II infused mice [10,16].
Moreover, adenoviral vectors encoding small interfering RNA to
selectively silence Nox2 or Nox4 (two isoforms of the NADPH oxidase)
expression in the subfornical organ demonstrate that both Nox2 and
Nox4 are required for the full vasopressor effects of brain Ang II [17,18].
One possible downstream mechanism of the activation of AT1R in the
SFO and subsequent production of ROS is the superoxide-mediated
intracellular calcium influx observed in neuroblastoma Neuro-2A
cells, which is inhibited by the adenoviral-mediated expression of a
dominant-negative isoform of Rac1 (AdN17Rac1), a critical component
for NADPH oxidase activation and superoxide production. These
evidences suggest that increased intracellular superoxide production in
the SFO is critical in the development of neurogenic hypertension by
increasing in sympathetic outflow via RVLM activation.

Ang-II

ROS

RVLM

Reactive Oxygen Species in the Rostral Ventrolateral

Medulla
The RVLM is a brainstem region that contains bulbospinal
neurons providing a major input to the preganglionic neurons of the
sympathetic nervous system [19,20]. The importance of the RVLM
for maintaining blood pressure in anesthetized animals had first been
documented 130 years ago [21]. However, only after the pioneer
studies performed by Guertzenstein and colleagues [22] suggesting that
supraspinal sympathetic vasomotor drive originates from the RVLM
that truly brought researchers attention to this brainstem area [22,23].
The RVLM receives inputs from the SFO and the PVN as discussed
earlier in this review, forming the so called SFO-PVN-RVLM pathway,
where Ang II seems to be the key neurotransmitter. For instance,
immunohistochemistry studies showing Ang II-like immunoreactive
neurons in PVN and terminals in RVLM support the concept that
angiotensinergic neurons in the PVN innervate the RVLM [24]. Of
note, angiotensin receptors, mainly AT1R subtype, are also present in
the RVLM [25] and plays an important role in altering the activity of
RVLM neurons [26]. For example, injection of Ang II into the RVLM
of the cat produces pressor response [27]. In addition, pharmacological
blockade of AT1R attenuates the pressor response to Ang II
microinjection in the RVLM of rats [28]. Furthermore, microinjection
of losartan in the RVLM attenuates the pressor response produced by
peripheral chemoreflex activation [13].
In experimental models of hypertension, the actions of Ang II
seem to be enhanced and AT1R seem to be tonically stimulated. In the
Spontaneously Hypertensive Rat (SHR), for example, it has been shown
that injection of Ang II in the RVLM produces a significantly greater
increase in blood pressure in SHR compared to normotensive rats [29].
Additionally, candesartan and valsartan, AT1R antagonists, injected in
the RVLM decreased blood pressure in SHR to normotensive levels but
had no effect in normotensive rats [29].
Regarding reactive oxygen species in the RVLM, our laboratory
and others have shown that Ang II-derived superoxide anions
accumulation in the RVLM is critical for the pathogenesis of neurogenic
hypertension (Figure 1) [12,17,18,30-32]. The increase of superoxide
anions leads to changes in ion channels, particularly calcium and
potassium channels, altering neuronal properties in RVLM resulting
in increase in sympathetic nerve activity and increase in blood
pressure [33]. To date, we have shown that chronic peripheral Ang II
infusion in mice produces a slow developing hypertension, which is
accompanied of superoxide accumulation in the RVLM and increased
sympathetic activity [30]. Similar results have been found in 2K1C rats
[31]. Interestingly, scavenging of superoxide by adenovirus-mediated
J Hypertens
ISSN: 2167-1095 JHOA an open access journal

ROS

Sympathoexcitation

Hypertension
Figure 1: Scheme showing the mechanism by which angiotensin II induces the
increase of ROS in the rostral ventrolateral medulla (RVLM) and modulate the
sympathetic flow leading to hypertension.

overexpression of Copper/Zinc Superoxide Dismutase (CuZnSOD)

in the RVLM prevents both the accumulation of superoxide and
the increase in sympathetic activity. Of note, we demonstrated in
rats that the association of dietary salt to Ang II infusion potentiates
the superoxide accumulation in the RVLM and the increase in
sympathetic activity caused by Ang II alone [12]. Furthermore, we
demonstrated that selective ablation of the AT1R in the RVLM using
the loxP-Crerecombinase technique also prevented hypertension and
superoxide accumulation in the RVLM of Ang II infused mice [30].
In addition to superoxide accumulation in the RVLM, it has been
documented that AT-1 mRNA expression and NAD(P)H oxidase
subunits are greater in the RVLM and PVN of 2K-1C rats when
compared to their sham control group, while the CuZnSOD expression
remains. Furthermore, injection of tempolinto the RVLM reduced
blood pressure and renal sympathetic activity in 2K1C but not in sham
rats unchanged [33].
Oxidative stress in the RVLM has also been associated to the
pathogenesis of the hypertension observed in chronic renal failure. For
instance, rats with chronic renal failure show increased p47phox and
gp91phox mRNA expression in the RVLM associated to a reduction of
AT1 mRNA in the brainstem compared to their controls [34].

Conclusions
Although the basic research using laboratory animals has
considerably contributed to unraveling the mechanisms underlying the
role of reactive oxygen species in the pathogenesis of hypertension, its
translation towards the human benefit is still matter of debate, mainly
because some clinical trials have failed in documenting the benefits
of antioxidant therapies [35]. Therefore, the challenge for the next
decades will be finding a path to safely interfere with reactive oxygen
species inside the humans brain, especially in hypertensive patients,
in order to prove the benefits of local antioxidant therapy as a reliable
treatment for neurogenic hypertension.

Volume 1 Issue 3 1000107

Citation: Carvalho AS, Guimaraes DD, Dantas BPV, Carreiro JN, Mendes-Junior LG, et al. (2012) Brain Angiotensin-II-derived Reactive Oxygen
Species: Implications for High Blood Pressure. J Hypertens 1:107. doi:10.4172/2167-1095.1000107

Page 3 of 3
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