Neuroscience & Medicine, 2013, 4, 284-289
Published Online December 2013 (http://www.scirp.org/journal/nm)
http://dx.doi.org/10.4236/nm.2013.44042
Open Access NM
Immunohistochemical Localization of Some Neurotrophic
Factors and Their Receptors in the Rat Carotid Body
Dimitrinka Y. Atanasova1,2, Nikolai E. Lazarov1,3*
1Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria; 2Institute of Experimental Morphology, Pathology and
Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; 3Department of Anatomy and Histology, Medical
University of Sofia, Sofia, Bulgaria.
Received October 14th, 2013; revised November 10th, 2013; accepted December 5th, 2013
Copyright © 2013 Dimitrinka Y. Atanasova, Nikolai E. Lazarov et al. This is an open access article distributed under the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original
work is properly cited.
ABSTRACT
The carotid body (CB) is a small neural crest-derived organ that registers oxygen and glucose levels in blood and regu-
lates ventilation. The most abundant cell type in the CB glomeruli is glomus or type I cells, which is enveloped by proc-
esses of sustentacular or type II cells. Growth and neurotrophic factors have been established as signaling molecules
played an important role in the development of the CB. To gain insight whether these signaling molecules are present in
the adult rat CB, we examined the expression and cellular localization of some neurotrophic factors and their corre-
sponding receptors in this organ by immunohistochemistry. The results showed the presence of nerve growth factor
(NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) as well as p75NTR,
tyrosine kinase A receptor (TrkA), tyrosine kinase B receptor (TrkB) and GDNF family receptor alpha1 (GFRα1) in the
adult CB. At the light-microscopical level, the immunoreactivity for NGF and both its low-affinity (p75) and high-af-
finity (TrkA) receptors was detected in the majority of glomus cells and also in a subset of sustentacular cells. BDNF
and its receptors, p75 and TrkB, were observed in the glomus cells, too. Remarkably, the immunohistochemical analysis
revealed that the neuron-like glomus cells, but not the glial-like sustentacular cells, expressed GDNF and GFRα1.
Taken together with prior results, it can be inferred that neurotrophins may be involved in the CB cell differentiation
and survival in adulthood, and may exert a potent glomic protective action as well. It is also presumable that GDNF
production by glomus cells plays a pivotal role in permitting long-term viability of CB grafts, which permits their po-
tential applicability in cell therapy as a promising tool in neurodegenerative disorders.
Keywords: Carotid Body; Immunohistochemistry; Neurotrophin Receptors; Trophic Factors; Rat
1. Introduction
The carotid body (CB) is the main peripheral arterial
chemoreceptor that detects blood levels of O2, CO2/H+
and glucose, and responds to their changes by regulating
breathing [1,2]. It is a small ovoid mass of tissue bilater-
ally located at the bifurcation of the common carotid ar-
tery, just before blood chemicals reach the brain, an or-
gan that is excessively sensitive to oxygen and glucose
deprivation. The CB is composed of two juxtaposed cell
types, neuron-like type I or glomus cells and glial-like
type II, also known as sustentacular cells, which are ag-
gregated in richly vascularized cell clusters, called
glomeruli [3]. Chemical and electrical synapses between
these cells allow for complex sensory processing in the
organ [2]. Furthermore, the principal type cells, i.e., the
glomus cell, contain secretory granules packed with pu-
tative transmitters and are thus considered the chemo-
sensory cells of the organ [1,4], while the type II cells, in
addition to their supporting role, have recently been as-
sumed to be the CB stem cells [5]. The neural crest ori-
gin of the CB suggests that it may require a trophic sup-
port for a continued survival and cell differentiation.
It has been demonstrated that CB chemosensitivity to
hypoxia develops during the early postnatal period. This
functional maturation partially depends on structural and
neurochemical changes, which are promoted by some
neurotransmitters, trophic factors and their receptors,
acting on the CB cell population in autocrine or paracrine
ways [6-8]. Besides, there is a convincing evidence that
neurotrophic factors from CB cells and nerve fibers also
*Corresponding author.

Immunohistochemical Localization of Some Neurotrophic Factors and
Their Receptors in the Rat Carotid Body
285
play an important role in maintaining the structural and
functional specialization of both CB components in
adulthood [9]. Indeed, recent studies have revealed that
glomus cells in the adult rat, of a neural crest origin, ex-
press a number of growth factors, implying their para-
crine-autocrine role in the CB [10,11].
In order to determine the survival requirements of the
parenchymal cells in this organ in adult life, we exam-
ined the immunohistochemical distribution and cellular
localization of some neurotrophic factors and their cor-
responding receptors in the CB of normal adult rats.
2. Materials and Methods
2.1. Animals and Tissue Preparation
The experiments were carried out on male Wistar rats
(300 g body weight). The experiments were conducted in
accordance with the ethical guidelines of the EU Direc-
tive 2010/63/EU for the protection of animals used for
scientific purposes following a standard protocol estab-
lished by the Bioethical Commission of the Biomedical
Research at the Institute of Neurobiology of the Bulgar-
ian Academy of Sciences. All efforts were made to
minimize the number of animals used and their suffering.
The rats were deeply anesthetized with Nembutal (50
mg/kg, i.p., Abbott) and transcardially perfused first with
0.05 M phosphate buffered saline (PBS), followed by 4%
paraformaldehyde in 0.1 M phosphate buffer (PB), pH
7.3. After perfusion, the carotid bifurcations were
quickly removed, both CBs were immediately dissected
out and the specimens were postfixed in the same fixa-
tive overnight at 4˚C. Thereafter, the tissue blocks were
embedded in paraffin and cut into 7 µm thick sections.
2.2. Immunohistochemical Procedure
The sections of CBs were deparaffinized with xylene and
ethanol, and processed for ABC (avidin-biotin-horse-
radish peroxidase complex) immunohistochemistry to
determine the neurotrophin profile of their chemorecep-
tor elements. Briefly, the endogenous peroxidase was
blocked with 1.2% hydrogen peroxide in absolute
methanol, followed by antigen retrieval in 10 mM citrate
buffer (pH 6.0) for up to 30 min in a microwave oven.
After washing in PBS, the sections were preincubated for
60 min at room temperature in 5% normal goat serum to
avoid unspecific staining. Between the separate steps, the
sections were rinsed with cold PBS/Triton X-100. Sub-
sequently, they were incubated in a humid chamber
overnight at 4˚C with the respective primary antibodies
(see Table 1 for suppliers and working dilutions). After
rinsing in PBS, the sections were incubated for 2 h at
room temperature with the appropriate secondary anti-
body, biotinylated goat anti-rabbit IgG (Dianova, Ham-
burg, Germany), goat anti-mouse IgG or rabbit anti-goat
IgG (both from Vector Laboratories, Burlingame, CA,
USA), at a dilution of 1:500, 1:250 or 1:200, respectively.
Following rinsing, the ABC complex (Vectastain Elite
Kit; Vector) was applied. After a color development with
diaminobenzidine as a chromogen for 3 to 5 min, the
sections were dehydrated in graded alcohols, cleared in
xylene, coverslipped with Entellan and air-dried.
2.3. Antisera Specificity Tests
We applied positive and negative controls to test the
specificity of the antibodies used in this study. For im-
munoreaction specificity testing, omission of the specific
primary antibodies by their replacement with PBS or
non-immune serum, at the same dilution as the primary
antiserum, was performed and no specific immunostain-
ing was found under these conditions. The specificities of
the antibodies used in this study have been described in
detail previously [12]. In particular, the primary antisera
Table 1. Primary antibodies used for immunohistochemistry.
Primary antiserum (Antigen) Host species/Type Supplier Cat. № Working dilution
NGF rabbit/polyclonal Santa Cruz sc-548 1:500
BDNF rabbit/polyclonal Santa Cruz sc-546 1:500
NT-3 goat/polyclonal Santa Cruz sc-13380 1:500
GDNF mouse/monoclonal Santa Cruz sc-13147 1:500
GFRα1 rabbit/polyclonal Santa Cruz sc-10716 1:500
p75NTR mouse/monoclonal DAKO M 3507 1:200
TrkA rabbit/polyclonal Santa Cruz sc-118 1:500
TrkB rabbit/polyclonal Santa Cruz sc-8316 1:500
TrkC rabbit/ polyclonal Santa Cruz sc-117 1:500
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Immunohistochemical Localization of Some Neurotrophic Factors and
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286
were preabsorbed for 2 h at room temperature or for 24 h
at 4˚C with the respective synthetic antigen at a concen-
tration of 20 or 200 µg/ml antiserum at its working dilu-
tion and the preabsorbed antisera were substituted for
non-absorbed antisera in the immunohistochemical pro-
cedure. Preabsorbed antibodies failed to stain any tissues
of the CB. The antibodies were further characterized with
tissue from regions known to contain the studied antigens.
Immunolabeled sections of various brain regions at the
level of the trigeminal sensory nuclear complex and the
trigeminal ganglion were used as positive controls for
each of the tested neurotrophic factors.
2.4. Image Processing and Analysis
After immunostaining, the specimens were examined and
photographed with a Nikon research microscope equipped
with a DXM1200c digital camera. The digital images
were saved in a TIF format, and matched for brightness,
contrast and removal of artifacts using Adobe Photoshop
CS3 software (Adobe Systems, Inc., San Jose, CA). The
number of immunopositive cells was determined in a
semiquantitative way for the two given cell populations.
The resultant values provide a relative quantity of the
immunostained glomus and sustentacular cells.
3. Results
3.1. Nerve Growth Factor Family
This small family of neurotrophic factors consists of a
group of neurotrophins, including the nerve growth fac-
tor (NGF), brain-derived neurotrophic factor (BDNF),
neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4, also
known as NT-5). They promote neuronal differentiation,
survival and plasticity by signaling via both a common
low-affinity (pan)neurotrophin receptor p75NTR and high-
affinity transmembrane receptors belonging to the tyro-
sine receptor kinase (Trk) proto-oncogene family. The
latter include TrkA, TrkB and TrkC, and exhibit binding
specificity. TrkA is a specific receptor for the NGF, TrkB
is a receptor for the BDNF and NT-4, while TrkC is a
receptor for NT-3. The number of immunopositive cells
and relative expression levels of the examined neurotro-
phins and their receptors are summarized in Table 2.
Our experiments showed that the majority of the adult
glomus cells and a subset of the sustentacular cells in the
rat CB were NGF immunopositive (Figure 1(A)). The
immunoreactive cells were spread throughout the CB.
The immunostaining in the glomus cells was strong
while that in the sustentacular cells was moderate and
primarily localized in their cytoplasmic processes sur-
rounding the glomus cells. None of the immunopositive
cells showed staining in their nuclei. Further, immunore-
activity for p75 (Figure 1(B)) and TrkA (Figure 1(C))
Table 2. Distributional pattern and relative expression lev-
els of neurotrophins and their receptors in the adult rat
carotid body.
Neurotrophic factors NGF BDNF NT3 GDNF
Glomus cells +++ +++ +++ +++
Sustentacular cells + + + −
Neurotrophin
receptors p75NTR TrkA TrkB TrkCGFRα1
Glomus cells +++ +++ +++ +++ +++
Sustentacular cells+ + + − +
(−), no immunopositive cells observed; (+), <50% immunopositive cells;
(++), 50% - 90% immunopositive cells; (+++), >90% immunopositive cells.
Figure 1. Immunohistochemical demonstration of members
of the NGF family and their receptors in the CB of adult
rats. Light photomicrographs showing that the cell clusters
exhibit immunoreactivity for NGF (A) and its low-affinity
p75NTR (B) and high-affinity TrkA (C) receptors. Note that
the immunostaining is observed in the cytoplasm of a large
number of glomus cells and in a subset of sustentacular cells.
The cytoplasmic processes of the latter are also endowed
with TrkA receptor (arrows). (D) Intense BDNF immunore-
activity in numerous glomus cells and scattered sustentacu-
lar cells. Expression of TrkB (E) and TrkC (F) receptor sub-
types is seen in virtually all glomus cells. Scale bar = 50 µm.
was detected in most of the glomus and in some susten-
tacular cells, as well as in nerve fibers within and around
the cell clusters. Similarly, NT-3 (not shown) and BDNF
immunostaining was observed in a lot of glomus cells
and a few sustentacular cells in the CB glomeruli (Figure
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Immunohistochemical Localization of Some Neurotrophic Factors and
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287
1(D)). In addition, almost all glomus cells were richly
endowed with TrkB (Figure 1(E)) and TrkC (Figure
1(F)) receptors.
3.2. Glial Cell Line-Derived Neurotrophic Factor
Family
Using antibodies directed against the glial cell line-de-
rived neurotrophic factor (GDNF) and its receptors, we
identified a large number of immunoreactive cells in the
CB, typically aggregated in evenly distributed cell clus-
ters. In particular, virtually all glomus (type I) cells in the
CB were immunopositive for GDNF (Figure 2(A)), with
no notable labeling of the elongated sustentacular (type II)
cells, which surrounded the glomeruli. Accordingly, all
groups of BDNF-immunoreactive cells were also immu-
nostained for the GDNF family receptor alpha-1
(GFRα1), which specifically binds the GDNF (Figure
2(B)). Our attempts to detect RET protein expression by
Figure 2. Immunohistochemical demonstration of GDNF
and its specific receptor in the CB of adult rats. (A) Repre-
sentative photomicrograph indicating the presence of
GDNF-immunoreactive cell groups in the CB glomeruli.
Note that only the glomus cells are immunopositive. (B)
High-resolution micrograph showing the expression of
GFRα1 receptor in the adult CB. A large number of type I
cells exhibit strong immunoreactivity for this receptor sub-
type with similar distributional patterns. (C) No immuno-
reactivity is observed in the section incubated with a pre-
absorbed primary antibody. Scale bars = 50 µm.
immunohistochemistry have failed so far, probably be-
cause its localization is mostly restricted to nerve endings
which are very few in the CB.
Control sections treated with the primary antisera pre-
absorbed with the respective synthetic antigens did not
display any staining (Figure 2(C)).
4. Discussion
The CB is the major arterial oxygen sensor providing
essential afferent input required for the maintenance of
breathing. There is compelling evidence that neurotro-
phic factors such as BDNF and GDNF, working in tan-
dem, are important regulators for the development of
peripheral chemoafferent neurons; the latter provide
hypoxic drive to the brainstem respiratory network [13,
14]. Previous studies have shown that many growth and
trophic factors are present in the glomus type I cells of
the mammalian CB (for a recent review, see [9]). Our
results provide immunohistochemical evidence that the
parenchymal cells in the adult rat CB express certain
neurotrophins belonging to the NGF and GDNF families
as well as their corresponding receptors. In particular,
here we demonstrate the occurrence of NGF, BDNF,
NT-3 and GDNF proteins in the vast majority of glomus
cells and a subset of sustentacular cells which are also
endowed with their cognate receptors p75, TrkA, TrkB
and GFRα1. Such expressional patterns are consistent
with the conclusion that the glomus cells may exert tro-
phic and/or regulatory impact on the adjacent CB cells in
adult life through neurotrophins, which play autocrine
and/or paracrine roles in promoting the survival, growth
and maturation of these cells [11,15].
In addition to their established role in maintaining the
structural and functional specialization of the CB in
adulthood, available evidence strongly suggests that
neurotrophins also promote neuronal precursor cell pro-
liferation and differentiation of distinct neural crest-de-
rived cells (see [16] and references therein). Indeed,
glomus and sustentacular cells, like sympathetic neurons
and chromaffin cells of the adrenal medulla, originate
from the neural crest and phenotypically resemble sym-
pathoadrenal chromaffin cells [17,18]. Our data confirm
prior findings demonstrating that NGF and its high-af-
finity receptor TrkA are preferentially expressed by the
CB glomus cells [10]. However, there is evidence that
the glomus cells do not depend on NGF (as do sympa-
thetic neurons) for survival in vitro and, thus, their
growth requirements are different from other cells of
neural crest origin [19]. In this respect, it has been pro-
posed that NGF interacts cooperatively with the basic
fibroblast growth factor to promote proliferation and sur-
vival of the CB cell population [20]. We have further
shown that NGF and TrkA immunoreactivity also occurs
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Immunohistochemical Localization of Some Neurotrophic Factors and
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288
in the sustentacular cells of the rat CB. It is well known
that NGF is an essential growth factor supporting stem
cell self-renewal outside the nervous system and, thus,
serves as a potential marker for progenitor cells. This
could explain the occurrence of immunoreactivity for this
neurotrophin and its receptors also in the sustentacular
cells which have lately been proposed to be the CB stem
cells giving rise to new glomus cells upon hypoxia [5,
21].
Several recent reports suggest that the expression of
BDNF, GDNF and their receptors in virtually all glomus
cells, which are known to be highly dopaminergic [22],
might account for their potential applicability in neuro-
logical cell therapy [23-26]. Moreover, it has been shown
that nerve fibers innervating the CB and dopaminergic
neurons in the rat petrosal ganglion (PG) also exhibit
BDNF immunoreactivity [27]. Hence, it is plausible to
assume that BDNF and GDNF potently promote the
survival of dopaminergic neurons like CB glomus cells,
and also exert a trophic effect on chemoafferent neurons
of the PG, acting as a target-derived survival factor in
adult life [27,28]. It has also been proposed that BDNF
selectively produced by glomus cells may support local
vascular morphogenesis in the CB [27] whereas GDNF
may act as a protector of catecholaminergic neurons
against toxic damage and oxidative stress [29]. In line
with this, we were able to demonstrate the presence of
GFRα1 in glomus cells of the adult rat CB whose pres-
ence in them was also confirmed by RT-PCR [23]. It is
likely that BDNF acts mainly via its specific receptor in
the adult rat CB.
Unlike the other neurotrophic factors of the NGF fam-
ily, NT-3 and NT-4 have been examined in less detail in
the adult rat CB. In the present study, we demonstrated
the presence of NT-3 and its specific receptor TrkC, but
not of NT-4, in the CB glomeruli. Nonetheless, we were
able to show that TrkB, which is a common receptor for
the BDNF and NT-4, is expressed in almost all glomus
cells. Besides, it is well known that NT-3 binds, though
with less affinity, to other related Trk receptors, TrkA
and TrkB, as well [16,30]. Accordingly, it seems that the
survival of glomus cells also depends on TrkB signaling.
The source of this signaling is, however, still remains
unidentified.
5. Conclusion
In conclusion, it can be inferred that the majority of the
glomus cells and a subset of the sustentacular cells in the
adult rat CB contain high levels of NGF, BDNF and
GDNF and their corresponding receptors. Taken together,
our results suggest that the principal CB cells depend on
certain locally produced trophic factors for their survival
in adult life. It is possible, however, that other neurotro-
phic factors previously reported to be present in the rat
CB [9,11] also play a role as survival factors for the
natural CB cell populations in adulthood. Given that sur-
vival depends on cell-cell interactions, glomus cells may
exert via the entire cocktail of neurotrophins present in
the trophic and/or regulatory control on the adjacent
neuron-like and glial-like cells in the CB, thus implying
their autocrine and paracrine action. Last but not least,
neurotrophins and in particular GDNF might prove to be
good candidates for the maintenance of the long-term
viability of CB grafts, thus permitting the successful de-
velopment of neurological cell replacement therapy.
However, additional experimental and clinical studies are
needed to determine whether this animal model is appli-
cable in humans.
6. Acknowledgements
This work was financially supported by the European
Social Fund and Republic of Bulgaria, Operational
Programme “Development of Human Resources” 2007-
2013 framework (grant BG051PO001-3.3.060048 from
04.10.2012 to DA). The authors wish to thank Professor
Anton Tonchev (Medical University of Varna) for the
generous gift of the primary antibodies, and Dr Angel
Dandov for his critical reading of this manuscript.
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