Plasma Levels of Vascular Endothelial Growth Factor After
Treatment for Cerebral Arteriovenous Malformations
Grace H. Kim, MD; David K. Hahn, BA; Christopher P. Kellner, BA; Zachary L. Hickman, MD;
Ricardo J. Komotar, MD; Robert M. Starke, BA; William J. Mack, MD; J. Mocco, MD;
Robert A. Solomon, MD; E. Sander Connolly, Jr, MD
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Background and Purpose—The role of abnormal angiogenesis in the formation and progression of cerebral arteriovenous
malformations (AVMs) is unclear. Previous studies have demonstrated increased local expression of vascular
endothelial growth factor (VEGF) in AVM tissue and increased circulating levels of VEGF in AVM patients. We sought
to further investigate the role of VEGF in AVM pathophysiology by examining changes in plasma VEGF levels in
patients undergoing treatment for AVMs.
Methods—Three serial blood samples were obtained from 13 AVM patients undergoing treatment: (1) before any
treatment, (2) 24 hours postresection, and (3) 30 days postresection. Plasma VEGF concentrations were measured via
commercially available enzyme-linked immunosorbent assay (ELISA). For controls, blood samples were obtained from
29 lumbar laminectomy patients.
Results—The mean plasma VEGF level in AVM patients at baseline was 36.08⫾13.02 pg/mL, significantly lower than that
of the control group (80.52⫾14.02 pg/mL, P⫽0.028). Twenty-four hours postresection, plasma VEGF levels dropped
to 20.09⫾4.54 pg/mL, then increased to 66.81⫾26.45 pg/mL 30 days later (P⫽0.048). The mean plasma VEGF
concentration 30 days after resection was no longer significantly different from the control group (P⫽0.33).
Conclusions—Plasma VEGF levels in 13 AVM patients were unexpectedly lower than controls, dropped early after AVM
resection, then significantly increased 30 days later. These results support the key role of abnormal angiogenesis in
AVM pathophysiology and suggest that a disruption in systemic VEGF expression may contribute to the natural history
of these lesions. (Stroke. 2008;39:2274-2279.)
Key Words: angiogenesis 䡲 cerebral arteriovenous malformation 䡲 plasma levels 䡲 vascular endothelial growth factor
C
erebral arteriovenous malformations (AVMs) are the
most common type of cerebrovascular malformation.4
They are grossly defined as an abnormal collection of dilated
arteries and veins containing dysplastic vessels in which
blood flows with no intervening capillary bed.29 These lesions
carry a life-long risk of hemorrhage of approximately 2% to
4% per year23 and can cause stroke in young adults.35
The mechanisms regulating the formation and progression
of AVMs remain largely unknown. AVMs appear to be
dynamic lesions, adding to their clinical unpredictability.
Endothelial cell turnover has been shown to be 7 times
greater in AVMs than in normal cerebral vessels by Ki-67
immunohistochemical analyses.13 Clinical evidence includes
observation of de novo generation of AVMs, enlargement and
regression of known lesions, and postoperative recurrence.6,8,47,48 Investigators have suggested that abnormal angiogenesis may play a central role in AVM formation and
progression and have indicated that vascular remodeling may
be mediated by angiogenic factors.12,20,52
In particular, vascular endothelial growth factor (VEGF), a
potent endothelial cell mitogen, is thought to play a key role.
Increased VEGF expression has been demonstrated in the
endothelium, subendothelium, and adventitia of resected
AVM specimens.14,15,20,22 More recently, one study reported
significantly elevated circulating VEGF levels in AVM patients compared to healthy controls.40
VEGF is a dimeric heparin-binding glycoprotein and mediates angiogenesis under both physiological and pathological
conditions.31 It is a highly specific and potent mitogen of
vascular endothelial cells, promotes endothelial cell survival and
migration, and increases microvascular permeability.9,10,17,30
Alternative splicing of VEGF mRNA gives rise to 5 different
isoforms with 121, 145, 165, 189, or 206 amino acids, the 3
shorter of which are secreted in soluble form.10,18,50 VEGF165
is the most abundantly secreted isoform in the body and
brain.1 The longer transcripts, VEGF189 and VEGF206, are
cell-associated and bound to heparin-containing proteoglycans in the extracellular matrix.10,19
Received December 11, 2007; accepted January 2, 2008.
From the Department of Neurological Surgery, Columbia University, College of Physicians & Surgeons, New York.
The first 2 authors contributed equally to this study.
Correspondence to Grace H. Kim, MD, Department of Neurological Surgery, Columbia College of Physicians and Surgeons, Neurological Institute of
New York, 630 W 168th St, Room 5-454, New York, NY 10032. E-mail [email protected]
© 2008 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.107.512442
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Kim et al
Plasma VEGF Levels in Patients Treated for Cerebral AVMs
Table 1.
Demographic and Clinical Characteristics of 13 Cerebral Arteriovenous Malformation Patients
No.
Age/Sex
Presentation
Location
Drainage
Feeding Artery
1
60 M
Incidental
2
R Frontal
Superficial
MCA/ACA
2
35 F
Headaches, visual aura
2
R Parieto-occipital
Deep
MCA/PCA
3
28 F
Arm pain and weakness
1.4
R
Temporo-occipital
Superficial
MCA/PCA
4
39 F
Headaches
3
L Parietal
Deep
ACA
5
67 M
Hearing loss
3.5
R Parietal
Superficial
MCA/ACA
6
36 F
Intracerebral hemorrhage
3
R Parietal
Superficial
MCA
7
32 F
Headaches, visual aura
3
R Frontal
Deep
MCA
8
52 M
GTC seizures, headaches
3
R Occipital
Superficial
MCA/PCA
MCA/ACA
Size (cm)
9
41 F
Incidental
3.5
L Frontal
Superficial
10
36 M
Incidental
3.8
R Fronto-temporal
Superficial
MCA
11
33 M
Seizures
3.2
L Frontal
Superficial
MCA/ACA
12
27 F
Seizures
3
L Temportal
Deep
MCA/PCA
46 F
Headaches
2
R Parieto-occipital
Superficial
ACA
13
2275
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ACA indicates anterior cerebral artery; GTC, generalized tonic-clonic; MCA, middle cerebral artery; PCA, posterior cerebral artery.
To further elucidate the role of abnormal angiogenesis in
AVMs, we conducted a prospective case– control study to
evaluate changes in plasma VEGF165 levels in patients undergoing surgical resection of AVMs. We aimed to assess VEGF
as a potential systemic marker of local angiogenic activity
and response to therapy. We hypothesized that increased
levels of plasma VEGF in AVM patients would significantly
decrease over time after definitive treatment of the lesion.
(ELISA) designed to measure VEGF165 levels (Quantikine, R&D
Systems Inc, Catalog No. DVE00, Lot 240685) according to the
manufacturer’s instructions. The assay exhibits no significant crossreactivity with other angiogenic factors and has a sensitivity of 9.0
pg/mL. Optical density was measured at 450 nm using an automated
microplate reader (Bio-Rad Laboratories, Model No. 680). VEGF
concentrations were normalized to patient plasma protein levels and
are reported as pg/mL.
Methods
Data were tested for normality and were found to be normally
distributed. Accordingly, data are presented as the mean⫾SEM
unless otherwise noted. Statistical differences between groups were
assessed using paired and unpaired Student t test where appropriate.
Repeated measures analysis of variance (ANOVA) was used to
compare differences in serial samples. Pearson’s correlation was
used to evaluate correlations between continuous variables. A
probability value of ⬍0.05 was considered statistically significant.
All analyses were performed using SPSS software (version 13.0,
SPSS Inc).
Patient Population
Thirteen patients with cerebral AVMs who were treated at Columbia
University Medical Center between July 2005 and September 2006
were consented and prospectively enrolled in this IRB-approved
study. Three serial blood samples were collected from each patient
throughout their treatment process: before any treatment (baseline
sample), 24 hours after surgical resection of the AVM, and 30 days
after surgery during in-office follow-up. For controls, 29 patients
undergoing lumbar laminectomy surgery during the same time
period were enrolled. In these patients, a single plasma sample was
obtained preoperatively. All control subjects were free of any known
history of AVMs.
Cerebral angiography was performed on all AVM patients before
their treatment according to standard protocol. All AVM patients
were treated by surgical resection and all patients, except one in
which the malformation had ruptured, underwent multi-staged endovascular embolization prior to resection. The number of embolization procedures received depended on the size, location, and
vascular morphology of the lesion. One (8%) patient did not undergo
any embolization procedures. Five (38%) underwent 1, 3 (23%)
underwent 2, and 4 (31%) underwent 3 embolizations. Measurements of platelet count, white blood cell count, and hemoglobin were
within the normal range in all AVM and control subjects. Characteristics of the AVM study population are shown in Table 1.
Laboratory Analysis of Plasma VEGF
Peripheral arterial blood samples were obtained from indwelling
arterial catheters or from venipuncture when arterial access was
unavailable and collected in sterile heparin-coated tubes. All blood
samples were centrifuged at 1957g at a temperature of 4°C for 15
minutes within 30 minutes of collection. Plasma was separated,
aliquoted, and stored at ⫺80°C until analysis was performed.
Plasma VEGF levels were determined using a commercially
available monoclonal antibody-based enzyme-linked immunoassay
Statistical Analysis
Results
There were 13 patients in the AVM group and 29 in the
control group. The mean age and standard deviation of AVM
patients was 40⫾12 years, whereas the mean age of the
control group was 61⫾12 years. In the AVM group, there
were 8 females and 5 males, whereas in the control group
there were 11 females and 18 males. Possible confounders
were analyzed by comparing VEGF levels in patients without
the confounder (AVM patients at baseline and control patients) to levels in patients with the confounder using a
Student t test. Table 2 shows that age, gender, history of
smoking, hypertension, and diabetes had no effect on plasma
VEGF levels.
Plasma VEGF Levels in Controls
The mean plasma VEGF concentration in controls was
80.52⫾14.02 pg/mL. There was no significant difference in
mean plasma VEGF levels between males and females
(72.11⫾17.70 versus 92.44⫾24.20 pg/mL, respectively,
P⫽0.49). No correlation was found between VEGF levels
and age (r⫽⫺0.034; P⫽0.86).
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August 2008
Table 2. Levels of Plasma VEGF (pg/mlⴞSEM) in AVM
Patients at Baseline and Control Patients According to Age,
Gender, and Clinical Comobridities
Variable
Present
n (%)
Absent
n (%)
P
Value
Age ⱖ60
87.69⫾20.30
20 (48)
47.75⫾8.85
22 (52)
NS
Male gender
71.02⫾15.43
23 (55)
61.62⫾16.1
19 (45)
NS
Smoker
75.75⫾19.20
16 (38)
61.23⫾13.53
26 (62)
NS
Hypertension
74.32⫾12.71
20 (48)
59.90⫾17.78
22 (52)
NS
Diabetes
mellitus
66.36⫾16.80
8 (19)
66.86⫾13.14
34 (81)
NS
SEM indicates standard error of the mean; NS, not significant.
Plasma VEGF Levels in AVM Patients
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The mean baseline plasma VEGF level in AVM patients was
36.08⫾13.02 pg/mL, significantly lower than the mean
plasma VEGF level in the control group (P⫽0.028, Figure 1).
There was no significant difference in VEGF levels between
males and females (51.34⫾31.42 versus 26.55⫾9.28 pg/mL,
respectively, P⫽.38). No correlation was found between
plasma VEGF level and patient age (r⫽⫺0.19; P⫽0.53) or
AVM size (r⫽0.40, P⫽0.18). No significant differences were
found in plasma VEGF levels according to patient clinical
presentation (headache, 23.26⫾11.76, seizures, 34.17⫾15.25,
asymptomatic, 74.40⫾50.87, P⫽0.45).
The Effect of Treatment on Plasma VEGF Levels
The mean plasma VEGF level 1 day after resection dropped
to 20.09⫾4.54 pg/mL, with a mean decrease from baseline of
15.99⫾14.20 pg/mL, which then increased to 66.81⫾26.45
pg/mL 30 days later, with a mean increase from baseline of
30.73⫾17.02 pg/mL (P⫽0.048, Figure 2). The mean plasma
VEGF concentration in AVM patients 30 days after surgery
was no longer significantly different from the mean plasma
VEGF concentration in the control population (66.81⫾26.45
versus 80.52⫾14.02 pg/mL, P⫽0.33, Figure 1).
Figure 1. Plasma VEGF levels in 29 control patients before
treatment and 13 AVM patients before any treatment and
1 month after embolization/resection.
Figure 2. Change in plasma VEGF levels in 13 AVM patients
from baseline to 1 day and 1 month after resection.
Discussion
Angiogenesis is a tightly regulated process maintained by a
delicate balance between proangiogenic and antiangiogenic
factors and is vital to brain development and repair. Abnormal expression of angiogenic factors has been repeatedly
observed to be involved in AVMs, making it increasingly
more evident that a disruption in angiogenic signaling systems is involved in the formation and progression of cerebral
AVMs.
The goal of the present study was to further our understanding of the angiogenic mechanisms regulating AVM
formation and clinical behavior in vivo by studying changes
in plasma VEGF levels in AVM patients undergoing definitive treatment for these lesions. A better understanding of the
role of abnormal angiogenesis in AVMs may lead to improved patient management and novel therapeutic options.
The results of our study were unexpected: plasma VEGF
levels at baseline in patients harboring AVMs were significantly decreased when compared to our control population.
Furthermore, plasma VEGF levels dropped 1 day after
combined treatment with embolization and resection, then
significantly increased to near control levels 1 month later
(Figure 2).
The cause for these changes in circulating VEGF levels has
been the source of much speculation. Since Robinson et al
examined cellular adhesion molecules in AVMs in 1995,36
more than 20 studies have contributed to the investigation of
AVM molecular biology. Enhanced VEGF expression in
particular has been repeatedly demonstrated in endothelial
and subendothelial layers of resected AVM specimens,14,15,20,22 whereas VEGF mRNA has been shown to be
upregulated in cells adjacent to AVMs.15 Some authors, on
the other hand, have reported associated VEGF receptors to
be downregulated in AVM tissues.12 A recent study reported
a significant increase in circulating VEGF levels in AVM
patients compared to healthy controls.40 Increased expression
of circulating VEGF has also been associated with other
cerebrovascular disorders including intracranial aneurysms,41
dural arteriovenous fistulas,21 and vasospasm after subarachnoid hemorrhage.5
VEGF expression is regulated by numerous factors, most
significantly hypoxia.42 It is also upregulated by insulin28 and
Kim et al
Plasma VEGF Levels in Patients Treated for Cerebral AVMs
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numerous growth factors and cytokines.7,37,51 The findings of
the present study suggest the presence of a negative feedback
system that may also help regulate systemic VEGF expression. In this model, elevated local VEGF production may
cause the release of a molecular mediator which activates an
inhibitory feedback mechanism that downregulates systemic
VEGF production. Alternatively, VEGF itself may mediate
its own inhibition via a negative feedback mechanism. This
model may also explain our finding of significantly increased
plasma VEGF levels after surgical resection of AVMs.
Removal of the focus of elevated VEGF production would
eliminate the stimulus for inhibition and thereby allow
systemic production of VEGF to resume over time to normal
levels as we found in our study. The cause for the drop in
VEGF levels immediately after treatment is unclear but may
represent an acute response to removal, in line with the
half-life of VEGF (reported to be 30 to 45 minutes).27,45
Similarly, Klisch et al found plasma VEGF levels in patients
with dural arteriovenous fistulas to decrease following endovascular treatment.21
Another possible explanation for our findings is the presence of an AVM “sink” in which circulating VEGF is trapped
by the AVM, thereby leading to low systemic levels and high
local levels of VEGF. After AVM resection, systemic VEGF
levels normalize over time secondary to removal of the
source of VEGF sequestration. In support of this theory, other
authors have shown VEGF receptors to be elevated within
AVM tissues.22 Although studies suggest that upregulated
VEGF mRNA in cells adjacent to AVMs accounts for the
elevated local VEGF protein levels,15 local production of
VEGF does not necessarily preclude the additional presence
of significant systemic sequestration.
Certainly, numerous other mechanisms could also account
for our findings. Increased VEGF expression postsurgically
may reflect local angiogenesis associated with recovery from
surgery attributable to local VEGF production at the wound
site. VEGF is a key component in wound healing31 and
increases in VEGF after surgery have been correlated with the
extent of incision.3 VEGF expression has also been shown to
be upregulated in endothelial cells, neurons, and astrocytes
within brain tissue after ischemic insult,25,34,44 likely promoted by hypoxia, as well as after contusion.49 Furthermore,
VEGF has been shown to have neuroprotective as well as
neurotrophic properties in several animal models.16,33,54 Finally, Sure et al has demonstrated significantly higher expression of VEGF in the endothelium of partially obliterated
(embolized) AVMs compared to nonembolized AVMs suggesting that resultant hypoxia or neoangiogenesis or both may
stimulate increased expression of VEGF.46,48 However, it is
difficult to determine which of, and to what degree, these
phenomena account for our findings.
The findings of the present study contrast with the recent
study by Sandalcioglu et al who found significantly elevated
levels of plasma VEGF in patients with AVMs compared to
healthy controls. This difference could be explained by a
difference in patient populations examined. Eight of the 17
AVM patients examined in this previous study presented with
hemorrhage of their AVM compared with only one patient in
the present study. Platelets, a major source of VEGF stor-
2277
age,11,38 release soluble VEGF into the circulation on activation during hemorrhage and clot formation.32,39,53 Moreover,
intracerebral hemorrhage from AVM rupture leads to mass
effect and local hypoxia, which can further stimulate VEGF
expression, potentially leading to higher measured VEGF
levels in their patient cohort.
Interpretation of our results may have been limited by the
selection of lumbar laminectomy patients as our controls.
This patient population is at greater risk for obesity and
hypertension, both of which have been correlated with
elevated VEGF levels.2,43 However, our control VEGF levels
correlate with the range of previously published normal
values (76.1⫾10.7 pg/mL).26 The inconsistency of arterial
versus venous blood sampling may also have limited the
interpretation of our results. Control, pretreatment, and immediate postoperative blood samples were arterial while
long-term follow-up samples were venous. The effect of
arterial versus venous blood sampling on the measurement of
circulating VEGF is unclear, although it merits consideration
in the interpretation of our results.
Further studies with a larger patient cohort and extended
time points are warranted to further elucidate the nature of
fluctuating VEGF levels in the context of AVM progression
and treatment as well as to identify the specific molecular
mediators involved in VEGF regulation. Finally, investigation of other angiogenic growth factors is also needed to
develop a clearer understanding of the mechanisms regulating
abnormal angiogenesis in cerebral AVMs.
Conclusion
Investigators have studied the role of angiogenesis in cerebral
AVMs in the hopes that it might provide insight into their
pathogenesis and suggest novel strategies for modification of
their behavior. Recently, authors have suggested the potential
benefit of antiangiogenic agents to modulate AVM behavior.24 However, our study underscores the complexity of
AVM pathophysiology and the still poorly understood nature
of angiogenesis in AVM formation and progression, highlighting the need for further clinical and experimental studies
before embarking on the development of clinically effective
antiangiogenic strategies.
Source of Funding
D.K.H. and C.P.K. were supported in part by a Doris Duke Clinical
Research Fellowship.
Disclosures
None.
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Plasma Levels of Vascular Endothelial Growth Factor After Treatment for Cerebral
Arteriovenous Malformations
Grace H. Kim, David K. Hahn, Christopher P. Kellner, Zachary L. Hickman, Ricardo J.
Komotar, Robert M. Starke, William J. Mack, J. Mocco, Robert A. Solomon and E. Sander
Connolly, Jr
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
Stroke. 2008;39:2274-2279; originally published online June 5, 2008;
doi: 10.1161/STROKEAHA.107.512442
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