Download The role of vascular endothelial growth factor and vascular stability

The Laryngoscope
C 2014 The American Laryngological,
V
Rhinological and Otological Society, Inc.
Contemporary Review
The Role of Vascular Endothelial Growth Factor and Vascular
Stability in Diseases of the Ear
Nyall R. London, MD, PhD; Richard K. Gurgel, MD
Objectives/Hypothesis: Vascular endothelial growth factor (VEGF) is a critical mediator of vascular permeability and
angiogenesis and likely plays an important role in cochlear function and hearing. This review highlights the role of VEGF in
hearing loss associated with vestibular schwannomas, otitis media with effusion, and sensorineural hearing loss.
Study Design: PubMed literature review.
Methods: A review of the literature was conducted to determine the role of VEGF in diseases affecting hearing.
Results: Therapeutic efficacy has been demonstrated for the anti-VEGF agent bevacizumab in vestibular schwannomas,
with tumor size reduction and hearing improvement in patients with neurofibromatosis type 2. The loss of functional Merlin,
the protein product of the nf2 gene, results in a decrease in expression of the anti-angiogenic protein SEMA3F through a Rac1–dependent mechanism, allowing VEGF to promote angiogenesis. Bevacizumab may therefore restore the angiogenic balance
through inhibiting the relative increase in VEGF. Many of the clinical findings of otitis media with effusion can be reproduced
by delivery of recombinant VEGF through transtympanic injection or submucosal osmotic pump. VEGF receptor inhibitors
have been demonstrated to improve hearing in an animal model of otitis media with effusion. VEGF affects both the inner ear
damage and repair processes in sensorineural hearing loss.
Conclusions: VEGF has an important role in vestibular schwannomas, otitis media with effusion, and sensorineural
hearing loss.
Key Words: VEGF, hearing, vestibular schwannoma, otitis media, sensorineural hearing loss.
Laryngoscope, 124:E340–E346, 2014
INTRODUCTION
Hearing occurs when sound is generated as an air
pressure wave that is mechanically transduced via the
ossicles in the middle ear to a fluid pressure wave in the
inner ear. The inner ear then converts the fluid pressure
wave to neural impulses that travel from the inner ear
along the central auditory pathways to the auditory cortex. Molecular interactions occurring in the cochlea and
along the central auditory pathway are critical for normal hearing. Vascular endothelial growth factor (VEGF)
is a critical mediator of vascular permeability and likely
plays an important role in aforementioned molecular
interactions of hearing.
From the Department of Internal Medicine, Program in Molecular
Medicine (N.R.L.), and Department of Oncological Sciences (N.R.L.), University of Utah, Salt Lake City, Utah; and Division of Otolaryngology–
Head and Neck Surgery (R.K.G.), University of Utah School of Medicine,
Salt Lake City, Utah, U.S.A.
Editor’s Note: This Manuscript was accepted for publication
December 9, 2013.
N.R.L. has previously been a paid consultant and was employed by
Navigen Pharmaceuticals.
The authors have no other funding, financial relationships, or conflicts of interest to disclose.
Send correspondence to Richard K. Gurgel, MD, Division of Otolaryngology–Head and Neck Surgery, University of Utah School of Medicine, Salt Lake City, UT 84112. E-mail: [email protected]
DOI: 10.1002/lary.24564
Laryngoscope 124: August 2014
E340
VEGF was originally identified as vascular permeability factor, a protein secreted by tumor cells that promotes the accumulation of ascites fluid.1 The VEGF
family of related proteins includes VEGF-A, VEGF-B,
VEGF-C, VEGF-D, and placenta growth factor.2 These
ligands interact with VEGF receptor tyrosine kinases
including (VEGFR)21, VEGFR-2, and VEGFR-3. In
addition, VEGF family ligands can interact with
neuropilin-1 and neuropilin-2, which are nonkinase
receptors known for their role in semaphorin signaling.
VEGF acts on endothelial cells to destabilize the
vascular barrier resulting in vascular leak and angiogenesis. This is achieved through dissolution of vascular
endothelial cadherin-mediated interendothelial cell
interactions.3 VEGF is essential in embryogenesis. Even
heterozygous loss of VEGF function causes abnormal
blood vessel formation and embryonic lethality.4,5 VEGF
also functions as a neurotrophic, neuroprotective, and
hematopoietic growth factor.6,7 Blocking VEGF function
has been utilized to treat cancer and ocular angiogenesis.8,9 In contrast, VEGF could potentially be utilized to
promote angiogenesis in clinical settings such as ischemic cardiovascular disease.10 Thus, VEGF function can
be a pathologic or beneficial agent depending upon the
clinical context.
Hearing loss causes significant individual morbidity
and associated societal burden. Understanding the role
London and Gurgel: VEGF and Vascular Stability in Hearing
of VEGF in hearing may lead to future treatments of
hearing loss. In this review we will highlight causes of
hearing loss including vestibular schwannoma (VS) and
otitis media with effusion (OME), in which VEGF contributes to disease pathology, as well as sensorineural
hearing loss (SNHL), in which VEGF may serve a therapeutic purpose.
VSs are benign neoplasms arising from Schwann
cells of the vestibular nerves. The most common symptoms reported by patients with VSs are hearing loss, tinnitus, and balance dysfunction.11 Standard therapies for
all VSs include active surveillance, radiation, and microsurgical resection.12–14 Although most VSs are sporadic
and unilateral, patients with the autosomal dominant
syndrome neurofibromatosis type 2 (NF2) often present
with bilateral VSs. All VSs, sporadic and syndromic, are
caused by a lack of functional Merlin, the tumor suppressor protein product of the nf2 gene, located on chromosome 22.15,16 Patients with NF2, however, have been
prioritized in using emerging targeted molecular
therapies because of the relatively high severity of their
disease burden.
Neovascularization has been implicated as a potential contributor to VS disease progression. Tumor size
has been correlated with extravasation of blood cells (an
indicator of permeability) as well as with quantity of
hyalinized vessels.17 VEGF expression as assessed by
semiquantitative immunohistochemical staining was
found in VSs to correlate with the tumor growth rate.18
Caye-Thomasen et al. also reported a correlation
between VEGF and VEGFR-1 concentrations and tumor
growth rate.19 Koutsimpelas et al. discovered a significant correlation of both VEGF mRNA and protein with
schwannomas growth index and microvessel density levels.20 Although these studies were conducted in sporadic
unilateral VSs, Saito et al. reported VEGF immunostaining in 8 of 10 schwannomas from NF2 or probable NF2
patients.21 Collectively, these studies suggest that VEGF
and angiogenesis play a significant role in VS disease
progression.
In a landmark trial, Plotkin et al. reported that
anti-VEGF therapy using intravenous (IV) bevacizumab,
a VEGF-neutralizing antibody, could improve hearing
and reduce tumor volume in NF2 patients.22 In this
study, 10 NF2 patients with progressively enlarging VSs
and poor surgical or radiation candidacy were treated
with bevacizumab. Six patients had an objective reduction in size of their tumors defined radiographically as a
volumetric reduction greater than 20%. Four out of these
six cases had a durable response at the last follow-up of
11 to 16 months after the initiation of treatment. An
improvement in hearing was also reported. Four of the
seven patients with diminished hearing at baseline had
improved word-recognition scores from 8% to 98%, 34%
to 76%, 0% to 40%, and 76% to 94%, respectively. The
result was observed as soon as 8 weeks after beginning
therapy and was durable for 11 to 16 months. A larger
follow-up study of 31 NF2 patients reported similar
findings of decreased tumor size and improved hearing.14 Similar results were observed in reports by two
other independent groups.23,24 To put the observed 11- to
16-month effect into perspective, other nervous system
tumors, such as recurrent glioblastoma, treated with
antiangiogenic therapy have a median time to progression of about 16 weeks. Furthermore, benign nervous
system tumors lack sensitivity to standard cytotoxic
chemotherapy,22 thus highlighting the notable effect of
anti-VEGF therapy in a benign tumor such as VS.
As systemic IV treatment with anti-VEGF therapy
poses many potential side effects, a recent study investigated endovascular targeted bevacizumab therapy after
mannitol blood-brain barrier disruption.25 The study
reported a short-term reduction in VS tumor size and
improved hearing after a single administration. These
results offer a potential therapeutic approach to circumvent side effects of systemic bevacizumab. Lastly, promising results including volumetric and hearing responses
from a 21-patient phase II trial have been reported
using lapatinib, a HER2/neu and EGFR inhibitor, to
treat NF2 patients with progressive VS.26
A possible explanation for the rapid effect of antiVEGF therapy in both schwannoma size and hearing
may be due to a reduction in permeability of peritumoral
blood vessels and associated vasogenic edema. For example, a significant correlation was observed between the
mean tumor apparent diffusion coefficient (a measure of
tissue edema on magnetic resonance imaging [MRI]) and
tumor shrinkage.22 One patient underwent sequential
dynamic contrast-enhanced MRI to directly evaluate
changes in tumor vascular permeability. At 3 months
post-treatment, vascular permeability decreased by 68%
and average vessel size by 70%. Although the data are
limited, these results support the theory that anti-VEGF
treatment has a profound effect on vascular permeability. A decrease in tumor size and adjacent cochlear neural edema could account for the improvement in
hearing.27
A limitation of Plotkin’s study was its inability to
determine whether the mechanism of action was
through vascular normalization or via a direct cytotoxic
effect on tumor cells.28 A subsequent series of in vitro
and in vivo experiments support the former mechanism
of vascular normalization. Wong et al. generated intracranial schwannomas in immunosuppressed mice via
subdural injection of human schwannoma cells.27 Bevacizumab decreased vascular permeability of the schwannomas by 43% within 24 hours, and the effect was
sustained at post-treatment day 6. Bevacizumab
decreased the vessel surface area 33% via a decrease in
vessel diameter and extended survival by 95%. Bevacizumab had little effect on the downstream intracellular
signaling in schwannoma cells in vitro including
p-EGFR, p-AKT, and p-ERK. Furthermore, necrosis
rather than apoptosis was noted in the schwannomas,
suggesting that cell death was a result of inadequate
vascular supply rather than apoptosis.
In giving further mechanistic insight, Wong’s study
also found that as a result of loss of functional Merlin,
there was downregulation in the semaphorin/neuropilin
Laryngoscope 124: August 2014
London and Gurgel: VEGF and Vascular Stability in Hearing
VEGF AND HEARING IN VS
E341
axis, an important regulatory pathway that suppresses
VEGF signaling.27 Tumor necrosis occurs when a tumor
has outgrown its blood supply. Necrosis is a characteristic finding of many solid tumors, which increase VEGF
expression to gain a more robust blood supply. As
schwannomas are not typically necrotic, the loss of semaphorin, rather than overexpression of VEGF, may be
responsible for promoting a proangiogenic state.
Merlin also regulates the Rac1 and p21 activated
kinase signaling pathways.29 This regulation maintains
contact inhibition with adjacent Schwann cells and regulates mitogenic activity.30 Merlin also regulates expression of class 3 semaphorins.31 A particular semaphorin,
SEMA3F, has been identified as an antiangiogenic factor
and has decreased levels in schwannomas. When
SEMA3F was reintroduced into schwannoma cells, there
was a decrease in tumor angiogenesis, vessels were normalized with increased pericyte coverage, vascular permeability was decreased, and cell survival was
increased.31 Thus, loss of functional Merlin results in a
decrease in expression of the antiangiogenic protein
SEMA3F, allowing for VEGF to promote angiogenesis.
Therefore, bevacizumab may restore the angiogenic balance through inhibiting the relative increase in VEGF
(Fig. 1).
Anti-VEGF therapy has primarily been used in NF2
patients because of the relatively higher disease burden
in these patients compared to those with sporadic, unilateral tumors. Using bevacizumab to treat patients
with sporadic, unilateral schwannomas would vastly
enlarge opportunities to study the medication’s clinical
efficacy. Given the slow progression of schwannomas and
expense of targeted molecular therapy, however, clinical
trials would be difficult to conduct. If the permeability
coefficient of individual tumors could be defined and correlation to treatment efficacy clearly established, perhaps patients at high risk for tumor growth or morbidity
could be selected to improve chances of therapeutic
effect. Future research efforts could be directed to evaluate anti-VEGF therapy as an adjuvant therapy to surgery, radiation, or perhaps other targeted molecular
therapies.32
VEGF AND HEARING IN OTITIS MEDIA
OME is a common cause of hearing loss in children, which impacts hearing at a variety of anatomic
locations, including most commonly the middle ear, but
also the cochlea and even the brainstem.33 The pathophysiology of OME is due to a chronic inflammatory
process.34 Subclinical bacterial infection or bacterial
components such as lipopolysaccharides (LPS), viruses,
or allergies incite a release of inflammatory cytokines
including tumor necrosis factor alpha, interleukin-1b
(IL-1b), interleukin-6, and interleukin-8.34–36 There is
also an increase in angiogenic and permeabilityinducing cytokines such as VEGF. Chronic inflammation and exposure to cytokines causes vascular leak,
resulting in an effusion in the middle ear space. The
effusion can be exacerbated by numerous factors including cytokines themselves. For example, IL-1b may con-
tribute to fluid retention by suppressing epithelial
sodium channel-mediated fluid absorption in middle ear
epithelial cells.37
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London and Gurgel: VEGF and Vascular Stability in Hearing
E342
Fig. 1. Treatment of vestibular schwannoma with bevacizumab.
(a) Under normal conditions, Merlin inhibits Rac1 resulting in
secretion of Sema3F. In this setting, inhibitory Sema3F levels are
counter balanced by vascular endothelial growth factor (VEGF).
(b) In vestibular schwannomas, loss of functional Merlin results in
increased Rac1 activity and decreased Sema3F secretion. Due to
loss of the inhibitory Sema3F balance, VEGF induces vascular
leak and angiogenesis. (c) Treatment of vestibular schwannomas
with bevacizumab likely restores an inhibitory balance by blocking
the positive VEGF signal. NF2 5 neurofibromatosis type 2. [Color
figure can be viewed in the online issue, which is available at
www.laryngoscope.com.]
Fig. 2. Otitis media with effusion (OME). Under normal conditions,
the middle ear is free from effusion. In OME, underlying eustachian tube dysfunction leads to a chronic inflammatory state
resulting in increased vascular endothelial growth factor (VEGF)
expression and angiogenesis, and vascular permeability leading to
effusion. [Color figure can be viewed in the online issue, which is
available at www.laryngoscope.com.]
Eustachian tube dysfunction has been proposed to
contribute to OME. The prevalence of OME is significantly higher in children due to the decreased angle and
diameter of the eustachian tube compared to adults.
When the eustachian tube is dysfunctional, the middle
ear is unable to equalize pressure from the nose and
atmosphere, resulting in negative pressure in the middle
ear following gas absorption.38–40 However, the actual
contribution of eustachian tube dysfunction in OME is
debatable.35 Neovascularization in the middle ear
mucosa with OME has been described and may occur in
response to mucosal proliferation. Neovascularization
may also be a contributing factor to disease pathology in
otitis media41,42 (Fig. 2), and obstruction of the eustachian tube has been demonstrated to increase VEGF
expression.43
Vascular endothelial growth factor expression has
been reported in the middle ear in response to inflammatory stimuli.44 Transtympanic injection of LPS in rats
induces VEGF expression. Turbid effusion was identified
in this model 12 hours postinjection and was preceded
by increased VEGF expression. Furthermore, VEGF
expression was identified in effusion fluid and middle
ear mucosa of human patients with otitis media.44
Another study found VEGF protein expression in 100%
of middle ear effusions in pediatric patients.45 Vascular
endothelial growth factor receptors VEGFR-1 and
VEGFR-2 are upregulated in middle ear mucosa after
LPS instillation.46 Significant upregulation in VEGF-A
and VEGFR-1 expression was reported in a mouse model
of otitis media induced by inoculation of nontypeable
Haemophilus influenza.47 Transtympanic injection of
recombinant VEGF itself in rats significantly increased
vascular permeability and increased middle ear effusion
Laryngoscope 124: August 2014
and mucosal inflammatory cell infiltration.48 Husseman
et al. investigated continuous submucosal delivery of
VEGF via osmotic minipumps in guinea pigs.47 This
infusion induced significant middle ear neovascularization. The study also showed that high-dose VEGF alone
is likely sufficient to produce OME.
Animal models are available to test the effectiveness of VEGFR inhibitors to improve hearing in OME.
One such model is the Junbo mutant (Jbo), a mouse
with spontaneous hearing loss due to chronic suppurative otitis media and otorrhea.49 These mice are a particularly useful model, as no other organ pathology or
immune deficiency has been noted.50 High levels of
VEGF has been reported in the bulla fluid of Jbo/1
mice. One study treated mice once daily with three different VEGFR inhibitors.50 Hearing was assessed from
day 28 to 56, and all three of these inhibitors significantly decreased hearing loss. Furthermore, one of the
inhibitors, PTK787, decreased the number of blood vessels in the middle ear mucosa and lymphangiogenesis.50
Although these results are encouraging in the management of OME, the small molecules used in this study
are not specific for VEGFR and target additional tyrosine kinases such as PDGFR-b and c-Kit.50 Further
investigation is warranted with compounds having
higher specificity to VEGF.
The Junbo mutant mouse is only one example of a
genetic model for chronic otitis media. A second murine
model of spontaneous chronic otitis media, known as the
Jeff mutant, also expresses high levels of VEGF in the
bulla fluid.50 The human homologue of the gene mutated
in the Jeff model is FBXO11.51 Interestingly, an association between polymorphisms in FBXO11 and otitis
media has been reported.52 An single-nucleotide polymorphism (SNP) association between FBXO11 and
severe otitis media was also seen in a cohort in Western
Australian children.53 Mechanistic studies have found
phospho-Smad2, a downstream regulator of transforming growth factor-b signaling, to be upregulated in Jeff
mice.54 How this cell signaling mechanism relates to the
demonstrated levels of VEGF in the bulla fluid of Jeff
mice is unknown.
Clinical trials using systemic anti-VEGF treatment
have inherent limitations due to the side effect profile of
anti-VEGF treatment, which includes delayed wound
healing, hemorrhage, and thrombosis. These potential
side effects may not be acceptable in the treatment of a
non-life-threatening disease such as OME.55 However,
localized anti-VEGF therapy via the transtympanic
route may be a viable treatment option that minimizes
systemic side effects.50 Similar localized anti-VEGF
treatment has proven useful for the vascular proliferation associated with macular degeneration.56
SNHL
SNHL includes dysfunction of the cochlea (sensory
hearing loss) or the vestibulocochlear nerve (neural
hearing loss). There are many genetic and environmental causes of SNHL. The most common form of SNHL is
age-related hearing loss or presbycusis. Presbycusis is
London and Gurgel: VEGF and Vascular Stability in Hearing
E343
noreactivity was decreased in the stria vascularis, spiral
ligament, and organ of Corti. Alternatively, in SwissWebster mice, which demonstrate stable hearing with
age, no difference in stria vascularis vessel density or
VEGF, VEGFR-1, or VEGFR-2 expression was found
with age.71 Thus, VEGF may play a protective role in
presbycusis.
It is unclear how beneficial VEGF therapy may be
for treating or preventing presbycusis. Although loss of
hair cells is the most common reason for SNHL, VEGF
did not have a protective effect on gentamicin-induced
auditory hair cell damage in vitro.72 Although there is a
paucity of literature pertaining to the role of VEGF in
various mechanisms of damage-induced SNHL, collectively the data suggest a potential beneficial role to
VEGF administration.
likely caused by an accumulation of acoustic damage
over time.57 Cochlear hair cell loss is the most common
reason for cochlear dysfunction. Hairs cells do not spontaneously regenerate in humans. Approaches to protect
hair cells include using antioxidants, neurotrophic factors, and inhibitors of cell stress pathways.57–59 Hair cell
regeneration or restoration with the use of stem cells is
an active area of research.60,61 Until human hair cell
regeneration is made possible, however, therapy to prevent hearing loss warrants further investigation.
Acoustic damage and ototoxic drug exposure have
been reported to cause significant cochlear vascular
alterations including changes in cochlear blood flow,
increased vascular permeability, and vasoconstriction.62,63 Some of these vascular changes may be permanent as observed in the chinchilla cochlea 45 days after
noise exposure.64 Noise exposure has also been reported
to structurally alter blood vessels by disrupting normal
pericyte-endothelial interactions, an important aspect to
maintaining the cochlear blood-labyrinth barrier.65
Although blocking VEGF may be warranted in VS
and OME, an increase in VEGF may be beneficial in settings of SNHL. Significantly less data are available in
the literature pertaining to the role of VEGF in SNHL
compared to what is known in VS and OME. Nonetheless, it is essential to address that which is known to
understand that VEGF does not always worsen disease
pathology in hearing loss. In contrast, VEGF may provide therapeutic benefit depending upon the disease context or timing of administration during disease
progression.
VEGF directly promotes axonal outgrowth and
enhances neuron survival.66,67 In a study investigating
noise-induced sensorineural damage in guinea pigs,
VEGF was up-regulated in the cochlea on both days 1
and 7 after noise exposure. In contrast, VEGFR-1 and
VEGFR-2 expression was unchanged. VEGF upregulation was most notably seen in the stria vascularis, spiral
ligament, and the spiral ganglion cells.68 As hearing
improved between days 1 and 7, and given VEGF’s spatial expression, it is possible that VEGF may be playing
a dual role in mediating both the response to vascular
damage and in the later repair process after noise exposure. Zou et al. analyzed VEGF expression after simulated mechanical drilling vibration damage to the inner
ear.69 Approximately 4 days after vibration-induced
hearing loss, the group observed VEGF immunostaining
located within the cochlea. VEGFR-1 expression was
unchanged, but VEGFR-2 expression was increased and
found at the basal end of the outer hair cells, Dieter
cells, Hensen cells, Claudis cells, basal membrane of the
organ of Corti, nucleus of the spiral ganglion cells, the
lateral wall of the scala tympani, and the spiral ligament.69 These findings suggest that VEGF functions to
repair cochlear damage at a cellular level.
Presbycusis may be caused by vascular abnormalities and altered VEGF expression. Picciotti et al.
showed decreased expression of VEGF in a mouse model
of presbycusis.70 This was achieved using C57BL/6 mice,
which are susceptible to rapid and severe age-related
hearing loss. As compared to young mice, VEGF immu-
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systems maintain vascular stability. Angiogenesis 2009;12:149–158.
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5. Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996;380:
439–442.
6. Gerber HP, Ferrara N. The role of VEGF in normal and neoplastic hematopoiesis. J Mol Med 2003;81:20–31.
7. Zachary I. Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals 2005;14:207–221.
8. Kim LA, D’Amore PA. A brief history of anti-VEGF for the treatment of
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Laryngoscope 124: August 2014
London and Gurgel: VEGF and Vascular Stability in Hearing
E344
CONCLUSION
VEGF has a well-defined role in vascular permeability and angiogenesis. Increased vascular destabilization and neovascularization may directly impact
hearing. Inhibition of VEGF or potentiation of its action
may provide clinical utility depending on the underlying
pathology. We have summarized anti-VEGF approaches
for treating VS and OME. The potential that VEGF
affects both the damage and repair processes in SNHL
merits further investigation. By addressing situations in
which VEGF plays a harmful role in disease pathology
(VS and OME) and contrasting this with the data pertaining to a potential beneficial role to the inner ear in
presbycusis or cochlear trauma, we have attempted to
demonstrate the multifaceted roles of VEGF on the ear.
Although clinical utility has been realized for anti-VEGF
therapy in treating VSs for patients with NF2, further
research may reveal additional clinical utility for targeting VEGF in other disorders that affect hearing.
Acknowledgments
The authors
assistance.
thank
Diana
Lim
for
graphical
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