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Membrane-transport systems in the fenestrated capillaries of the area postrema in rat and calf.

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THE ANATOMICAL RECORD PART A 279A:664 – 670 (2004)
Membrane-Transport Systems in the
Fenestrated Capillaries of the Area
Postrema in Rat and Calf
CRISTIANO BOMBARDI, ANNAMARIA GRANDIS,
ROBERTO CHIOCCHETTI, MARIA LUISA LUCCHI,* EMILIO CALLEGARI,
AND RUGGERO BORTOLAMI
Department of Veterinary Morphophysiology and Animal Productions, Faculty of
Veterinary Medicine, University of Bologna, Ozzano dell’Emilia, Italy
ABSTRACT
The capillaries of the area postrema (AP) lack the morphological peculiarity of the blood-brain barrier (BBB), and the AP neurons are considered
located outside the BBB. Using the immunofluorescent method, we have
investigated the expression of membrane transport systems that are instrumental to the BBB function, such as caveolin-1, -2, P-glycoprotein, and
glut-4, in the capillary endothelium of the rat and calf AP. The expression
of these molecules was verified after fibronectin immunostaining of the
microvessels. Both in the rat and calf, caveolin-1, -2, and P-glycoprotein
were expressed in the AP capillaries. A quantitative analysis revealed that
the proportion of the capillary profiles expressing these transport systems
was very close to 100% of the fibronectin immunolabelled profiles. On the
contrary, none of the AP capillaries showed glut-4 immunoreactivity. The
present investigation demonstrates that the endothelial layer of the AP
capillaries, in spite of the paracellular passage of polar molecules through
the leaky tight junctions and fenestrations, could be an active interface
which is able to control the entry of a wide range of blood-borne compounds
into the brain by means of specific mechanisms, including an efflux pump.
©
2004 Wiley-Liss, Inc.
Key words: receptor-mediated transport; efflux pump; immunohistochemistry; fenestrated endothelium; circumventricular organs; area postrema
The entry and distribution of organic compounds and ions
into the central nervous system depends on the blood-brain
barrier (BBB), which is made up of brain microvessel endothelial cells. These cells form a continuos layer; they are
characterized by low pinocytosis activity (Reese and Karnovsky, 1967) and are connected to each other by extensive
and complex tight junctions that prevent the paracellular
passage of most polar molecules (Kniesel and Wolburg, 2000;
Petty and Lo, 2002). Moreover, they are equipped with specific enzymatic and membrane transport systems in both
blood to brain (influx) and brain to blood (efflux) directions
(Tamai and Tsuji, 2000). Therefore, the passage across the
BBB results biochemically and locally selective. However, in
some cerebral areas referred to as circumventricular organs
(CVOs), the endothelial capillary layer lacks the morphological peculiarity of the BBB, because of the fenestrated endothelial cells and the numerous pinocytic vesicles (Dempsey,
©
2004 WILEY-LISS, INC.
1973; Klara and Brizzee, 1975, 1977; Coomber and Stewart,
1986; Casali et al., 1989; Lucchi et al., 1989; Gross, 1992), as
well as the leaky tight junctions (Petrov et al., 1994). Therefore, the CVOs are traditionally considered outside the BBB
Grant sponsor: Ministero dell’Istruzione, dell’Università e della
Ricerca (M.I.U.R).
*Correspondence to: Professor Maria Luisa Lucchi, Facoltà di
Medicina Veterinaria, Università di Bologna, Dipartimento di
Morfofisiologia Veterinaria e Produzioni Animali, Via Tolara di
Sopra 50, 40064 Ozzano dell’Emilia, Italy. Fax: 0039 051-792956.
E-mail: lucchi@vet.unibo.it
Received 15 August 2003; Accepted 15 February 2004
DOI 10.1002/ar.a.20041
Published online 3 June 2004 in Wiley InterScience
(www.interscience.wiley.com).
665
TRANSPORT SYSTEMS IN AREA POSTREMA CAPILLARIES
TABLE 2. Calf area postrema*
TABLE 1. Rat area postrema*
Double
immunolabellings
Fibronectin Caveolin-1
Fibronectin Caveolin-2
Fibronectin
P-glycoprotein
Fibronectin Glut-4
N/mm2a
SD
347.83
347.17
346.67
344.83
351.17
349.83
346.17
0
⫾ 53.76
⫾ 53.93
⫾ 47.17
⫾ 46.97
⫾ 45.23
⫾ 45.18
⫾ 46.00
⫾0
%
Double
immunolabellings
N/2mm2a
Fibronectin Caveolin-1
99.81
Fibronectin Caveolin-2
99.47
99.62
Fibronectin
P-glycoprotein
Fibronectin Glut-4
0
*Quantitative values of capillary density in double immunolabelling.
a
Mean value of the number of AP immunoreactive capillary
profiles in six rats.
SD, standard deviation; SE, standard error of mean; %, percentage of capillaries profiles expressing the second antigen.
and no data are available on the presence of receptor mediated vesicular transport and of efflux/influx transporters in
the endothelial cells of these cerebral areas.
In order to verify a transporter mediated permeation in
the capillaries of the CVOs, we have investigated on the
fenestrated endothelium of the area postrema (AP) the expression of caveolin-1 and -2, P-glycoprotein, and glut-4. As it
is well known, these membrane-transport systems are able
to catalyze a selective transport in the BBB endothelium
(Dehouck et al., 1997; Ikezu et al., 1998; Ngarmukos et al.,
2001; Bendayan et al., 2002; Virgintino et al., 2002a,b).
The AP represents a chemosensitive CVO involved in
emetic response and many other functions, such as neurosecretion, cardiovascular and respiratory regulation,
blood osmoreception, control of renal function, and caloric
homeostasis (Leslie, 1986; Borison, 1989). Also, the AP is
considered an important center for the integration of metabolic and hormonal control of nutrient intake (Edwards
et al., 1981; Ritter et al., 2000; Riediger et al., 2002). The
AP neurons have afferent and efferent connections (Morest, 1967; Vigier and Portalier, 1979; Manni et al., 1982;
Leslie, 1986; Koga and Fukuda, 1992; Ferguson, 1992;
Yuan and Barber, 1993) and are capable of serving as
targets for specific endogenous blood-borne humoral messengers. In fact, prolactin (Mangurian et al., 1999), angiotensin (Consolim-Colombo et al., 1996), and vasopressin
(Jurzak and Schmid, 1998) receptors have been evidenced
on the AP neurons.
This study has been performed on rat and calf because
they exhibit different behaviors to circulating emetic
agents. In fact, the i.v. injection of apomorphine causes the
expulsion of acidic abomasal contents back to preabomasal compartments (“internal vomiting”) in ruminants
only, while in rat it causes “clinical vomiting” (Eiler et al.,
1981).
MATERIAL AND METHODS
Tissue Preparation
The medulla oblongata was removed from six adult
Sprague Dawley rats (350 – 430 g), killed under ethical
approval of the Committee of Animal Experimentation of
Bologna University, and from three calves (3–12 months),
butchered at a public slaughter-house. It was dissected
rostrally and caudally to the obex to take out a sample at
the level of the area postrema. The samples were im-
608.33
606.67
609.67
607.00
604.67
602.67
619.33
0
SD
⫾ 15.50
⫾ 16.01
⫾ 17.67
⫾ 16.46
⫾ 14.19
⫾ 15.18
⫾ 13.61
⫾0
%
99.73
99.56
99.67
0
*Quantitative values of capillary density in double immunolabelling.
a
Mean value of the number immunoreactive capillary profiles
counted in the left (1 mm2) and the right (1 mm2) sides of the
AP in three calves.
SD, standard deviation; SE, standard error of mean; %, percentage of capillaries profiles expressing the second antigen.
mersed in 2-dimethylbutane frozen in liquid nitrogen.
Cryostatic transverse serial sections (7 ␮m in thickness)
were collected on glass slides coated with poli-L-lysine
(Sigma-Aldrich, St. Louis, MO) and briefly fixed in cool
acetone (–20°C).
Immunohistochemistry
The sections of each AP were subdivided into four
groups and submitted to fluorescent double immunolabelling for: fibronectin and caveolin-1 (first group); fibronectin and P-glycoprotein (second group); fibronectin and
glut-4 (third group); and fibronectin and caveolin-2 (fourth
group). For each animal, the immunohistochemistry for a
given second antigen was performed every fourth section
of the series.
Fibronectin immunostaining was used as a capillary
marker (Gobel et al., 1990; Theilen and Kuschinsky, 1992)
to visualize the existing AP capillary profiles and to verify
the expression of the second antigen in the same structures.
After washing in phosphate-buffered solution (0.01 M
PBS), the sections were incubated for 30 min in 3% normal
donkey serum (S30; Chemicon, Temecula, CA) in PBS and
treated with 0.5% Triton X-100 in PBS for 30 min. Thereafter, the sections of the first, second, and third groups
were incubated in a mixture of mouse anti-fibronectin
(diluted 1:100 in PBS; EP5: Santa Cruz-8422, Santa Cruz,
CA), and then rabbit anti-caveolin-1 (diluted 1:100 in
PBS; N-20: Santa Cruz-894), rabbit anti-P-glycoprotein
(diluted 1:200 in PBS; H-241: Santa Cruz-8313), and rabbit anti-glut-4 (diluted 1:200 in PBS; H-61: Santa Cruz7938) antibodies for 1 hr, respectively. After washing in
PBS, the sections were incubated for 45 min with a mixture of FITC-conjugated donkey anti-mouse (diluted 1:200
in PBS; Jackson Immuno Research 715-095-150, West
Grove, PA) and TRITC-conjugated donkey anti-rabbit (diluted 1:200 in PBS; Jackson Immuno Research 711-025152), as secondary antibodies.
The sections of the fourth group were incubated in a
mixture of rabbit anti-fibronectin (diluted 1:1000 in PBS;
DAKO 0245, Glostrup, Denmark) and goat anti-caveolin-2
(diluted 1:200 in PBS; N-20: Santa Cruz-1858) antibodies
for 1 hr. After washing in PBS (3 ⫻ 10 min), the sections
were overlaid with a mixture of AMCA-conjugated donkey
666
BOMBARDI ET AL.
Fig. 1. Area postrema of the rat. Paired images of capillaries immunostained for: a) fibronectin-FITC and
a1) caveolin-1-TRITC, bar ⫽ 20 ␮m; b) fibronectin-AMCA and b1) caveolin-2-FITC, bar ⫽ 20 ␮m; c)
fibronectin-FITC and c1) P-glycoprotein-TRITC, bar ⫽ 20 ␮m.
anti-rabbit (diluted 1:200 in PBS; Jackson Immuno Research 705-155-147) and FITC-conjugated donkey antigoat (diluted 1:200 in PBS; Santa Cruz-2024) as secondary
antibodies and incubated for 45 min.
The incubations were performed at room temperature in a
humid chamber. Control sections were prepared by omitting
the primary antibodies. After washing in PBS (3 ⫻10 min),
the slides were mounted with buffered glycerol, pH 8.6.
Fluorescent Microscopy
The sections were examined on an epifluorescent microscope (Axiophot, Carl Zeiss, Oberkochen, Germany)
TRANSPORT SYSTEMS IN AREA POSTREMA CAPILLARIES
667
Fig. 2. Area postrema of the calf. Paired images of capillaries immunostained for: a) fibronectin-FITC and
a1) caveolin-1-TRITC, bar ⫽ 50 ␮m; b) fibronectin-AMCA and b1) caveolin-2-FITC, bar ⫽ 20 ␮m; c)
fibronectin-FITC and c1) P-glycoprotein-TRITC, bar ⫽ 50 ␮m
equipped with fluorescent filter combinations for the detection of FITC, TRITC, and AMCA. The images were
recorded by using a Polaroid DMC digital camera (Polaroid Corp., Cambridge, MA) and DMC2 software. The
images were further processed using Adobe Photoshop
software (Adobe Systems, San Jose, CA).
The AP microvessels were first located by the presence
of the fluorophore that labels fibronectin; then the filter
was switched to visualize the fluorescence that labels the
second antigen. In this way, paired images of the same
field were recorded with the X 25 objective. Random sampling of areas within a given section was considered; 32
668
BOMBARDI ET AL.
paired images, derived from no less than 16 different
sections of each group, were recorded.
Quantitative Analysis
For each double immunolabelling, an overall area of 1
mm2 was analyzed in each rat However, since the AP is a
bilateral organ in ruminants, an area of 1 mm2 was considered in each calf in each side (for a total of 2 mm2). In
this reference space, the capillary profiles immunolabelled
for fibronectin and for the second antigen, respectively,
were counted to have the density of both (N/reference
space). The counts were accomplished by two laboratory
members using a blind approach. Data were pooled by
summing the values from each animal, and the percentage
of the capillaries expressing the second antigen (caveolin-1, -2, P-glycoprotein, and glut-4) was determined (Tables 1 and 2). In addition, a linear regression analysis was
performed for each second antigen.
RESULTS
In the first, second, and fourth groups of sections, the
AP capillary profiles were double-immunolabelled (Figs. 1
and 2). In the third group of sections, none of the fibronectin immunolabelled AP capillary profiles showed glut-4
immunoreactivity that, on the contrary, was present in
the capillaries of the adjacent cerebral areas.
From the quantitative analysis, it was found that in
both the rat and calf AP, the proportion of the capillaries
immunostained for caveolin -1, -2, and P-glycoprotein,
respectively, was always very close to 100% of the fibronectin immunostained profiles. In fact, no significant
differences were found among the counts of the fibronectin
immunostained AP capillary profiles and that of the capillaries also expressing the second antigen (Tables 1 and
2). Moreover, the linear regression analysis showed that
the AP capillary profiles expressing the second antigen
had a significant positive association with the fibronectin
labelled ones both in the rat and calf (Figs. 3 and 4).
No immunofluorescence was observed in the control sections processed after omission of the primary antibodies.
DISCUSSION
This study demonstrates the presence of caveolin-1, -2,
and P-glycoprotein, and the absence of glut-4 in the fenestrated capillary endothelial layer of the rat and calf AP.
Since fibronectin is a reliable marker of the brain microvessels (Gobel et al., 1990; Theilen and Kuschinsky,
1992), the quantitative analysis shows that caveolin-1, -2,
and P-glycoprotein are expressed in a proportion very
close to 100% of the AP capillaries.
As it is well known, caveolin-1 and -2 are the principal
components of the caveolae. They may regulate specific
biological actions mediated by receptors (Schlegel and
Lisanti, 2001) and are implicated in the receptor-mediated
uptake and transcytotic vesicular transport of molecules,
such as albumin (Pelkmans and Helenius, 2002), LDL
(Dehouck et al., 1997), and insulin (Ikezu et al., 1998).
Therefore, their expression can account for the large number of shuttle vesicles (50 –100 nm in diameter) described
in the endothelial cells of the AP capillaries (Coomber and
Stewart, 1986).
In addition, the expression of P-glycoprotein provides
evidence of a carrier-mediated efflux transport system in
the AP fenestrated endothelial cells. P-glycoprotein is a
Fig. 3. Area postrema of the rat. Graphs showing density of fibronectin (FIBRO) immunolabelled capillaries in relation to the number of capillaries expressing: a) caveolin-1 (CAV-1); b) caveolin-2 (CAV-2); c) Pglycoprotein (P-GLY). The level of significance was set at P ⬍ 0.05. A
solid triangle shows duplicate points.
TRANSPORT SYSTEMS IN AREA POSTREMA CAPILLARIES
669
and/or prevent nonessential compounds from entering the
cells (Borst et al., 1993).
Recent studies on different cell types demonstrate that
caveolin-1 and -2 can form a stable hetero-oligomeric complex (Scherer et al., 1997). Moreover, an interaction between caveolin-1 and P-glycoprotein has been demonstrated in the BBB endothelial layer (Demeule et al., 2000;
Bendayan et al., 2002; Virgintino et al., 2002a,b). Since
the statistical analysis shows that virtually all the rat and
calf AP capillary profiles are immunostained for caveolin-1, -2, and P-glycoprotein, it seems reasonable to assume that these molecules can also interact in the fenestrated endothelial cells of the AP.
The absence of glut-4, as well as of glut-1 (Young and
Wang, 1990), i.e., of glucose transporters, in a glucoreceptive cerebral area, such as the AP (Ritter et al., 2000;
Riediger et al., 2002), can be explained with the transendothelial passage of glucose across the leaky tight junctions and fenestrations of the AP endothelial cells.
On the basis of this study, it is possible to conclude that
the AP capillary endothelial layer, in spite of its paracellular permeability, could represent a dynamic interface
that is able to regulate the movement of a wide range of
blood-borne compounds by means of different mechanisms, including an active efflux process.
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Fig. 4. Area postrema of the calf. Graphs showing density of fibronectin (FIBRO) immunolabelled capillaries in relation to the number of
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P-glycoprotein (P-GLY). The level of significance was set at P ⬍ 0.05.
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