World Journal of Neuroscience, 2012, 2, 68-73 WJNS
http://dx.doi.org/10.4236/wjns.2012.22010 Published Online May 2012 (http://www.SciRP.org/journal/wjns/)
Hypertension effects on p73 expression in the rat
circumventricular organs and cerebrospinal fluid
Emilia M. Carmona-Calero1,2, Ibrahim González-Marrero1,2, Manuela Castañeyra-Martin2,
Juan M. González-Toledo1, Leandro Castañeyra-Ruiz2, Héctor de Paz-Carmona1,
Agustín Castañeyra-Ruiz2, Lidia Ruiz-Mayor1, Agustín Castañeyra-Perdomo1,2*
1Departamento de Anatomía, Facultad de Medicina, Universidad de La Laguna, Tenerife, Islas Canarias, Spain
2Departamento de Biotecnología, Instituto de Investigación y Ciencias de Puerto del Rosario, Fuerteventura, Islas Canarias, Spain
Received 14 December 2011; revised 30 January 2012; accepted 16 February 2012
ABSTRACT
It has been reported that spontaneously hypertensive
rats (SHR) show ventricular dilation, changes in CSF
proteins and variations in the circumventricular organs
(CVO) such as: the subcommissural organ (SCO), the
subfornical organ (SFO) and the area postrema (AP)
which are located in the walls of the third and fourth
ventricles. On the other hand, p73 proteins are pre-
sent in cells of the central nervous system (CNS) such
as circumventricular structures and the neuroepithe-
lium which are altered in ventricular dilation. The
purpose of the present work is to study the TAp73
isoform expression in the circumventricular organs
(CVO) and their variations in ventricular dilatation
and arterial hypertension. Brains and cerebrospinal
fluid (CSF) from control Wistar-Kyoto rats (WKY)
and SHR were used. The paraffin sections containing
the CVO were immunohistochemically processed with
anti-TAp73 and by western blot, p73 bands in the CSF
and circumventricular organ extract were also identi-
fied. The western blot study showed bands marked
with p73 in the CSF and CVO, the p73 band expres-
sion was bigger in the SHR than in the WKY rats. We
also found stronger markings in the SFO, SCO and
AP of the hypertensive rats than in the WKY rats. It
could be concluded that hypertension in the SHR
produces alterations in the relationship between the
p73 protein, circumventricular structures and CSF.
Keywords: Circumventricular Organs; p73; CSF;
Hypertensive Rats
1. INTRODUCTION
Ritter and Dinh [1] described that spontaneously hyper-
tensive rats present a progressive increase in ventricular
size from 4 to 56 weeks of age, and in some SHRs ven-
tricle size increased to 270% of control and such ven-
tricular dilation could be produced by a loss of grey and
white matter similar to what occurs in hydrocephalus, for
this reason, certain systemic and behavioural signs which
are concomitant with hypertension in the SHR may be
attributable to hydrocephalus and its neuropathological
correlates [1]. It has also been observed in previous
studies [2,3] that the increase in ventricular size can be
qualitatively observed after 15 weeks of postnatal age. On
the other hand, alterations of the subcommissural organ,
subfornical organ in the hypertensive and hydrocephalic
rats were also observed [4-7].
The subcommissural organ (SCO) is a cerebral struc-
ture associated with the circulation and composition of
the CSF, which secretes glycoprotein into the CSF where
its greater part is condensed and forms Reissner’s fibre
(RF), and the other minor part remains soluble in the
CSF. The human SCO has a great development during
the foetal life [8,9], variations in the CSF and SCO have
been reported in different kinds of hydrocephalus [4,10,
11]. Alterations of the SCO in hydrocephalic mice and
rats have been described, Takeuchi et al. [12] de- scribes
agenesis of the SCO and the posterior commissure (PC)
in hydrocephalic mice, Irigoin et al. [11], Rodriguez et al.
[4] and Carmona-Calero et al. [7] found alterations in the
secretion of the SCO in induced and spontaneously hy-
drocephalic rats. In addition, alterations in the secretions
of cerebrospinal fluid proteins from the SCO have been
described in spontaneously hypertensive rats [6].
The Subfornical Organ (SFO) is a circumventricular
organ located below the commissure fornici, entering the
rostral wall of the third ventricle [13], and is a neuroglio-
vascular structure containing neurons, glia and plexus of
fenestrated capillaries. The SFO is characterized by the
absence of a blood-brain barrier [14]. The SFO has con-
nections with the brain regions involved in the central
regulation of drinking, salt appetite, blood pressure and
*Corresponding author.

E. M. Carmona-Calero et al. / World Journal of Neuroscience 2 (2012) 68-73 69
cardiovascular function, such a region is the anteroven-
tral region of the third ventricle which is involved in the
control of drinking behaviour [15,16].
The area postrema located at end of the fourth ventri-
cle under the obex [13] also contains neurons, glia and
fenestrated capillaries, and does not have a blood-brain
barrier. The AP functions are related with cardiovascular
regulation and the catecholaminergic system as well as
with the anteroventral region of the third ventricle [17,18].
The role of p73 is significant in the central nervous
system development, since the p73 knock-out mice pre-
sent hippocampal dysgenesis, cortical hypoplasia and hy-
drocephalus, meaning that p73 plays an important role in
the different parameters regulating brain development
[19]. The transactivating isoforms of p73 (TAp73) are
similar to p53 acting as transcription factors inducing
cellular apoptosis; on the other hand, the N-terminal
truncated isoforms (ΔNp73) can inhibit the transcript-
tional function of p53 and TAp73 [20]. It has recently
been reported that TAp73 is present in the SCO and CSF
where it could play an important role in the maintenance
of the ventricular wall and in the development of neu-
roepithelium proliferation [21].
Bearing in mind that SHRs present ventricular dilation,
alterations in the circumventricular organs and CSF pro-
teins variations, the purpose of the present work is to
study the expression of p73 in the CSF, SCO, SFO and
the AP in arterial hypertension and ventricular dilation.
2. MATERIAL AND METHODS
Brains and cerebrospinal fluid (CSF) from 16 control
Wistar-Kyoto rats (WKY) and 16 spontaneously hyper-
tensive rats (SHR) from Charles River Laboratories
España S.A. (Barcelona, Spain) of 12 months of age were
used. The rats were anesthetized with chloral hydrate
(200 l/100g of body weight at 160 mg/ml) and 100 l
of CSF from the cistern magna of each animal was ex-
tracted before sacrifice. Extracts of circumventricular or-
gans and CSF were prepared from 12 rats from each group
which were processed by protein electrophoresis accord-
ing to Laemmli [22] (sodium docecyl sulfate-poly-
acrylamide gel electrophoresis SDS-PAGE, 5% - 15%
gradient). Four rats from each group were fixed by in-
tracardiac perfusion with Bruin’s fluid, dehydrated and
embedded in paraffin under standard conditions. Brains
were cut into four serial coronal and sagittal sections of
10 μm thickness. One of the serial coronal sections was
stained by the Klüver-Barrera method.
The polyclonal antibody against TAp73 (Ab 14430,
Abcam, Cambridge, UK) was used as the primary anti-
body. In each rat brain of each group, the sections at the
level of the SCO, SFO and AP from the WKY and SHR
were simultaneously incubated in the same coupling jar
and each jar contained: anti-p73 1:1000. Incubation was
for 24 h at room temperature, followed by “DAKO”
StreptABCcomplex/HRP Duet, Mouse/Rabbit procedure.
The peroxidase reaction product was visualized using
diaminobenzidine reaction.
Western blots of CSF protein and SCO, SFO and AP
extract protein were performed. The membranes with the
blotted proteins were incubated in tris-saline (TBS)
non-fat milk 5% for 60 minutes and then incubated in the
primary antibody anti-p73 1:1000 overnight. Anti-mouse
IgG labelled with peroxidase (PIERCE) was used as the
secondary antibody at a dilution of 1:80,000 for 1.45 h at
room temperature. The peroxidase reaction products
from western blot were visualized by quimioluminis-
cence (PIERCE). The primary antibody was omited to
validate the control method specificity. The immunohis-
tochemistry slides were converted to digital images by
using an LEICA DMRB photomicroscope with an
LEICA DC 300 F camera (Gemany). Image analysis was
completed in Image J (v. 1.43 u, NIH, Bethesda, MD,
USA). The “Mean Gray Value” was measured from the
selected nuclei for all stained tissue and membranes. This
value gives the average stain intensity in grayscale units
for all threshold pixels. A single-factor analysis of vari-
ance (ANOVA) was used for the immunohistochemistry
statistical study, which was conducted using the IBM
SPSS statistic 19 software.
3. RESULTS
Hydrocephalus was clearly observed at 12 months of age
in the SHRs by comparing the ventricular size of these
SHRs with the normal ventricular size observed in WKYs
of 12 months of age (Figu r e s 2 (K), (L)).
3.1. Immunohistochemistry
The expression of the TAp73 in the SCO of WKY rats
was present in apical perinuclear parts of ependymal and
hypendymal cells and some marks were even observed in
the ventricle (Figures 1(A), (C); 2(I), (J)). A significant
increase of TAp73-ir (F1-6 = 134.975 P < 0.05) was ob-
served in the different parts of the ependymal and
hypendymal cells in the SCO of the SHR (Figures 1(B),
(E); 2(M), (N); 4).
The cytoplasm of cells in the ependyma layer was
marked with TAp73-ir and this was also found in several
body neurons and in perivascular spaces in the SFO of
the WKY rats (Figures 1(A), (D); 2(A), (B)). A note-
worthy increase of TAp73 expression (F1-6 = 224.615 P <
0.05) in the parenchyma and neurons was found in the
SFO hypertensive rats (Figures 1 (B), (F); 2(E), (F); 4).
The AP showed immunoreactive material in several
neurons and perivascular spaces in the WKY rats (Figures
2(C), (D)) and a slight and not significant increase in the
immunoreaction intensity was observed in neurons and
ependyma in AP of the SHRs, (Figures 2(G), (H); 4).

E. M. Carmona-Calero et al. / World Journal of Neuroscience 2 (2012) 68-73 70
ChP
SCO
SFO
SFO
III
VENTRICLE
ChP
D
C
PC
PC
F
F
ChP
III
VENTRICLE
D
C
WKY
SHR
SCO
A
B
SCO
SCO SFO
F
C
E
D
SFO
Figure 1. Sagittal section photographs of the rat brain immunostained with
anti-TAp73. A: WKY rats; B: SHR rats; C: SCO, D: SFO of WKY rats; E:
SCO; F: SFO of SHR rats. WKY: control Wistar-Kyoto rats; SHR: spontane-
ously hypertensive rats; SCO: subcommissural organ; SFO subfornical organ;
ChP choroid plexus; F fornix; PC posterior commissure; III ventricle; C caudal;
D dorsal. Bar = 80 μm.
SHR
SFO
FSFO
F
SFO
F
AP
AP
AP AP
ChP
SCO SCO
PC
ChP
III III
I
J
M
N
A
B
D
C
E
F
G
H
WKY
ChP
K
L
F
F
AC
AC
SHR
WKY
WKY
WKY
WKY
WKY
WKYSHR
SHR
SHR
SHR
SHR
SHR
ChP
III
LV
LV
ChP
ChP
ChP
SFO
SFO
ChP
Figure 2. Photographs of the rat circumventricular organs immunostained
with anti-TAp73. Coronal view of the SFO; A, B WKY rats; E, F SHR rats.
Coronal view of the SCO; I, J WKY rats; M, N SHR rats. Sagittal view of the
AP: C, D WKY rats, G,H SHR rats. Coranal view of the rat brain at the AC
level: K, WKY rats, L SHR rats. Bar = 50 μm (A,E,I,M,C,G); 150 μm (B,F,J);
80 μm (D,H); 300 μm (K,L). WKY: control Wistar-Kyoto rats; SHR: sponta-
neously hypertensive rats;AP: area postrema; SFO: subfornical organ; SCO
subcommissural organ; OP optic chiasma; F fornix; III ventricle; ChP choroid
plexus; LV lateral ventricle; AC anterior commissure.

E. M. Carmona-Calero et al. / World Journal of Neuroscience 2 (2012) 68-73 71
3.2. Western Blot
The anti-p73 reaction in the immunoblotting showed two
bands of 65 and 90 kDa in SCO, SFO and AP extracts
which were more intense in the SCO (F1-10 = 214.809 P <
0.05) of the SHRs WKY rats. There were also two bands
of the same molecular weight in the cere- brospinal fluid,
and the intensity of the reaction was greater in the CSF
of the SHRs than in the WKY rats (Figures 3, 5).
CSF
SHRWKY
SFO APSCO
WKYWKY WKYSHR SHRSHR
Figure 3. TAp73 western blot of the circumventricular organ
extracts and cerebrospinal fluid. WKY: control Wistar-Kyoto
rats; SHR: spontaneously hypertensive rats; AP: area postrema;
SFO: subfornical organ; SCO subcommissural organ; CSF:
cerebrospinal fluid.
*
*
Figure 4. Densitometry of the circumventricular organs im-
munostained with anti-TAp73, *significant differences: SFO
F1- = 224.615 P < 0.05; SCO F1-6 = 134.975 P < 0.05.
6
**
Figure 5. Densitometry of anti-TAp73 in the western blot of
the circumventricular organ extract and CSF. *significant dif-
ferences: SCO F1-10 = 214.809 P < 0.05; WKY: control Wis-
tar-Kyoto rats; SHR: spontaneously hypertensive rats; AP: area
postrema; SFO: subfornical organ; SCO subcommissural organ;
CSF: cerebrospinal fluid.
4. DISCUSSION
The SHRs present an elevation of blood pressure from 10
weeks of age and a progressive increase of ventricular
size from 4 to 56 weeks of age (Ritter and Dinh, 1986).
Martinez-Peña y Valenzuela et al. [6] described that ven-
tricular dilation can be qualitatively observed after 26
weeks of postnatal age, this is clearly present in 38 week
old SHRs in the present work and a large ventricular
dilation at 12 months of age was observed. On the other
hand, ventricular enlargement occurred in the absence of
p73, and consequently neuronal degeneration and tissue
mass decreased, a phenomenon which is also observed in
the degenerating human brain [21]. In addition, the
balance between different isoforms of p73 is essential for
the survival and cell death during brain development
[21,23]. Pozniak et al. [20], indicating that p73 isoforms
in the CNS are necessary for maintaining, at least, some
populations of adult brain cells, therefore a balance in
p73 isoforms is necessary for maintaining normal central
nervous system development, a balance which could be
altered in the SHR. The results of this study shows that
chronic hypertension causes an increase in the reaction
anti-p73 in the SFO of the SCO, and AP. Increased
anti-p73 reaction in the CVO of the SHR compared to
WKY rats was also observed after immunoblotting,
which showed a p73-ir band in extracts of CVO, which
was also stronger in the SHR. Moreover, p73 also
identified bands in CSF, consistent with the conclusion
that one of the isoforms of p73 is glycosylated and
secreted into the cerebrospinal fluid [20]. These results
could mean that hypertension and ventricular dilation
induce alterations of the TAp73 in the CVO, in addition
the TAp73 in the CSF may play an important role in the
development of the ependymal layer and the neuroepithe-
lium [24], which could explain the higher variations of
TAp73 expression found in the subcommissural organ
(SCO) and in the CSF.
Recent study showed that mice lacking the TAp73 iso-
form, have alterations in dentate gyrus of the hippocampus
[25], an important neurogenic structure in the adult brain.
These results, and the relations among the p53 family,
stem cells, and aging, suggest that TAp73 may play a role
not foreseen in maintenance of neural stem cells. This
hypothesis has been tested and shows that TAp73 en-
sures normal adult neurogenesis by promoting the long-
term maintenance of neural stem cells [26].
High blood pressure in SHRs is accompanied by ven-
triculomegaly and variations of TAp73 expression in
circumventricular organs and the CSF, therefore, if hy-
pertension aggravates the aging brain and impairs mem-
ory, attention and abstract reasoning [27-29], and that the
TAp73 in the CSF plays an important role in maintaining
the adult ependyma, ventricular wall, and neural stem

E. M. Carmona-Calero et al. / World Journal of Neuroscience 2 (2012) 68-73 72
cells, one might conclude that TAp73 appears to play a
role in maintaining the ventricular system and circum-
ventricular structures, and that alterations of TAp73 CSF
levels in hypertension may be an important factor that
should be taken into account in the development of pre-
mature aging and cognitive disorders.
5. ACKNOWLEDGEMENTS
This work was supported by the Fundación Canaria de Instituto de
Investigacion y Ciencias de Puerto del Rosario (INIPRO) project n 01/08.
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