The Role of Macrophage in the Pathogenesis of Brain
Arteriovenous Malformation
Li
Ma, Yi Guo, Yuan-Li Zhao, Hua Su
Li
Ma, Yi Guo, Hua Su, Center for Cerebrovascular Research, Department of
Anesthesia and Perioperative Care, University of California San Francisco, San
Francisco, California, United States of America
Li
Ma, Yuan-Li Zhao, Department of Neurosurgery, Beijing Tiantan Hospital,
Capital Medical University, Beijing, China
Yi
Guo, Department of
Neurosurgery, Affiliated Hospital of Hebei University, Baoding, China
Yuan-Li
Zhao, China National
Clinical Research Center for Neurological Diseases, Beijing, China
Yuan-Li
Zhao, Center of Stroke,
Beijing Institute for Brain Disorders, Beijing, China
Yuan-Li
Zhao, Beijing Key
Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing,
China
Correspondence to: Hua Su, MD, Center for Cerebrovascular Research,
Department of Anesthesia and Perioperative Care, University of California, San
Francisco, 1001 Potrero Ave, Box 1363, San Francisco, CA 94110, United States
of America
Email: hua.su@ucsf.edu
Telephone: +1-415-206-3162
Received: March 5,
2015
Revised: May 1, 2015
Accepted: May 5, 2015
Published online: July 6, 2015
ABSTRACT
Brain
arteriovenous malformation (BAVM) is an important risk factor for intracranial
hemorrhage, especially in children and young adults. Inflammation has been
implicated in BAVM lesion progression. Among various inflammatory components,
macrophage is one of the major inflammatory cells present in human ruptured and
unruptured BAVM and in the BAVM lesions of animal models. The role of
macrophage in BAVM pathogenesis is not fully understood. In this review, we
summarize recent studies on macrophages and introduce a non-invasive imaging
protocol as a potential tool for detecting macrophage in BAVM and predicting
the risk of BAVM rupture.
© 2015 ACT. All
rights reserved.
Key words: Brain arteriovenous malformation; Pathogenesis;
Inflammation; Macrophage
Ma L, Guo Y, Zhao YL, Su H. The Role of
Macrophage in the Pathogenesis of Brain Arteriovenous Malformation. International Journal of Hematology Research 2015; 1(2): 52-56
Available from: URL: http://www.ghrnet.org/index.php/ijhr/article/view/1097
INTRODUCTION
Brain arteriovenous malformations (BAVMs) are complexes of tortuous,
tangled vessels located in the brain parenchyma, in which a loss of normal
capillary bed results in fistulous connections between arteries and veins.
Abnormal arteriovenous shunting contributes to high flow in focal vascular
structures, especially in the tangled nidus and draining veins. BAVMs have an
abnormal wall structure and are at risk of rupture, often resulting in
catastrophic hemorrhage[1]. Most patients experience their first
hemorrhage between the ages of 10 and 60[2,3]. BAVMs are prevalent
in about 0.01% of the general population[2,4], and the majority of
those are sporadic. Approximately 5% of BAVMs are familial or associated with
other abnormalities, such as hereditary hemorrhagic telangiectasia (HHT) or
Sturge-Weber syndrome[5,6].
Although BAVMs
are thought to be congenital lesions with occasional de novo growth, the
etiopathogenesis is still not fully understood. Accumulated studies on the
molecular and cellular biology of BAVMs have indicated that inflammation plays
an important role in the progression and rupture of BAVM[7-10].
Macrophages have been found in the vascular wall as well as adjacent brain
parenchyma of unruptured, previously untreated BAVMs[10,11]. The
expression of macrophage migration inhibitory factor (MIF), a key activation
factor of macrophages, is increased in BAVM and is associated with
proliferation and apoptosis of vascular cells[12]. Macrophages are
thought to promote BAVM progression and rupture through secretion of
pro-inflammatory cytokines (including tumor necrosis factor-α [TNF-α],
interlukin-6 [IL-6], and vascular endothelial growth factor [VEGF]), that
potentiate pathological angiogenesis and abnormal vascular remodeling[13].
Macrophages
and BAVM lesion progression
The development of cerebral vasculature is a result of vasculogenesis
and angiogenesis. Current evidence of BAVM etiology focuses primarily on
abnormal angiogenesis, which occurs in two phases: (1) vascular endothelial
cell proliferation and migration, in which VEGF and matrix metalloproteinase
(MMPs) are key mediators; (2) vascular stabilization, during which endothelial
cells form capillary tubes, intercellular junctions are strengthened, and
pericytes and the precursors of smooth muscle cells are recruited to the newly
formed endothelial tubes[14].
Abnormalities
during these two phases of angiogenesis can ultimately lead to the development
of BAVM. Although the most well-known function of brain macrophages involves
immunity and barrier genesis, the perivascular and blood-derived macrophages
could also be involved in angiogenesis[15]. During the development
period, macrophages interact with tip cells to chaperone vascular anastomoses[16].
LysM-Cre-mediated deletion of Notch1 in macrophages causes abnormal anastomoses
between angiogenic sprouts in the retina[17]. Delta-like 4 (Dll4)
positive tip cells interact in close proximity with Notch1-expressing
macrophages at vascular branch points.
Previous
studies have shown that macrophages are the major bone marrow-derived cells
(BMDCs) recruited to the VEGF-induced brain angiogenic focus[18].
Since the number of BM-derived macrophages in VEGF-induced brain angiogenic
regions peaks earlier than angiogenesis, the macrophages likely play a role in
the activation of angiogenesis. Further studies have revealed that 80% of the
infiltrated BM-derived macrophages express MMP-9, indicating that macrophages’
involvement in angiogenesis occurs during vascular endothelial cell migration
by activating MMP-9[18,19].
Evidence
obtained through analyses of surgically-resected BAVM suggests that BAVM is an
active angiogenic and inflammatory lesion rather than a static congenital
anomaly[9]. Endothelial proliferation increases in BAVM. BAVMs also
have higher levels of MMP-9, IL-6, VEGF-A, and angiopoietin-2 (ANG-2)[20-22].
Ang-2, the predominant form of angiopoietin in inflamed tissues and a
functional antagonist of Tie-2, promotes vascular destabilization[23].
In the presence of VEGF, the destabilized vessels undergo angiogenic changes
and sprout to form new vessels[24]. Expression of Tie-2 is thought
to be restricted to endothelial cells[23,25]. However, recent
studies reveal that Tie-2-expressing monocytes and macrophages present in human
peripheral blood as a response to elevated Ang-2 in inflamed tissues, where
they then play an important role in modulating cytokines implicated in
angiogenesis and inflammatory processes[26]. Therefore, the
macrophages in BAVM are very likely to be associated with vascular
destabilization. The role of Tie-2-expressing macrophages in BAVM pathogenesis
would be a worthy subject of investigation in future studies.
Current
knowledge regarding the development of BAVM comes from animal models that were
generated in the adult mouse through conditional deletion of hereditary
hemorrhagic telangiectasia (HHT) causative genes, endoglin (Eng) and
activin-like kinase 1 (Alk1, ACVLR1), in combination with focal angiogenic
stimulation. HHT is an autosome-dominate disorder, and HHT patients have a higher
prevalence of BAVM development than the normal population. Adult mice with Eng
or Alk1 deletion develop BAVM after brain focal angiogenic stimulation. The
BAVM in these mice mimic many phenotypes of human sporadic BAVMs, and therefore
are the most useful models for studying BAVM pathogenesis[27-30].
Recent studies
in bAVM animal have revealed that after angiogenic stimulation, similar degrees
of cerebrovascular dysplasia developed in Eng+/- mice and wild-type (WT) mice
transplanted with Eng+/−bone marrow (BM). In addition, the dysplasia in Eng+/−
mice could be partially rescued by transplantation of WT BM[31].
This suggests that Eng deficiency in BM is sufficient to cause cerebrovascular
dysplasia in the adult mouse after angiogenic stimulation. Macrophages are the
major BM-derived cells detected in the brain angiogenic foci in mice[32],
and in human surgical resected BAVM specimens with or without a history of
hemorrhage or previous treatment with embolization or radiosurgery[9,10,18].
These findings suggest that macrophages are directly involved in BAVM
development. However, deletion of Eng in LysM positive macrophages during the
embryonic developmental stage did not cause BAVM formation even after brain
focal VEGF stimulation[30,33]. Therefore, gene deficiency in
macrophages alone might not be sufficient for BAVM formation. Macrophages,
however, do not constitute a “pure” population, since they can be divided into
distinct subgroups based on their functions and gene expression profiles[34].
It is possible that certain macrophage subgroups, rather than all macrophages,
contribute significantly to BAVM development.
Macrophages
can undergo classical M1 activation or alternative M2 activation[35].
The M1 phenotype is characterized by the expression of high levels of
pro-inflammatory cytokines, and reactive nitrogen and oxygen intermediates. M1
macrophages promote Th1 response, and have strong microbicidal and tumoricidal
activity. In contrast, M2 macrophages are considered to exhibit
anti-inflammatory activity, and play an important role in tissue remodeling and
wound repair. Therefore, they may be crucial for tissue homeostasis to be
restored[36].
A study by
Hasan et al[37] suggests that an imbalance of M1/M2
macrophages plays a role in cerebral aneurysm rupture. In addition, iron
overload induces macrophage polarization toward pro-inflammatory M1[38].
BAVM is an active inflammatory lesion, and about 30% of unruptured BAVMs have
microhemorrhage, which increases iron deposition and pro-inflammatory mediators[7].
Future studies should explore the association between macrophage polarization
and BAVM progression and hemorrhage.
Macrophage and BAVM hemorrhage
Unfavorable outcomes of BAVM are attributed mostly to hemorrhage;
however, not all cases of BAVM hemorrhage are symptomatic and caused by
vascular rupture. Silent intra-lesional hemorrhages in BAVMs have been reported[39,40].
About 14-20% of BAVM patients without hemorrhagic history exhibit signs of
prior hemorrhage[40]. Recent studies found that 30% of resected
surgical specimens from patients with unruptured BAVMs and without history of
hemorrhage contain microscopic evidence of hemosiderin deposition in the
vascular wall or intervening stromal tissue[10,11]. Further analyses
suggest a strong association between old silent hemorrhage and the risk of
future symptomatic hemorrhage[10].
The casual
relationship between macrophage infiltration and clinically symptomatic hemorrhage
as well as silent hemorrhage is still unclear. Silent hemorrhage and other
inflammatory cytokines could activate and recruit macrophages into the lesions.
Inflammation, including macrophage infiltration, could impair the vascular
integrity and consequently induce silent or clinically symptomatic hemorrhage.
The factors
that initiate monocyte activation and macrophage infiltration are still
unclear. Macrophage infiltration could be initiated during the early
development of BAVMs, since CD68+ cells present in unruptured BAVM
specimens that have no hemosiderin deposition. However, unruptured BAVMs with
silent hemorrhage (iron deposition) tend to have more macrophages than those
without it[11]. Histological examination of BAVM in patients and in
mouse BAVM models demonstrates that the degree of hemosiderin or iron
deposition (hemorrhagic product) correlates positively with the number of
macrophages in the lesion[10,28]. These data suggest that
microhemorrhage is one of the factors that induce macrophage infiltration in
BAVM.
The BAVM
vessels in an Alk1-deficient BAVM model have less mural cell coverage,
increased fibrin and iron deposition, and small pockets of extravasated red
blood cells in the brain parenchyma. Therefore, impaired vascular integrity
could cause erythrocyte exudation and enhance macrophage infiltration in BAVM.
Vascular
destabilization induced by inflammation or macrophage infiltration could result
in erythrocyte extravasation from vascular walls. The hemoglobin breakdown
products from the extraverted erythrocytes will, in turn, attract more
macrophages. This process results in chronic inflammation that drives abnormal
vascular remodeling, which further impairs vascular integrity.
Potential
use of macrophages as a biomarker for BAVM future hemorrhage
Since macrophages are associated with BAVM hemorrhage and rupture, the
macrophage load might be used to identify BAVM at risk of rupture. A
noninvasive means to detect macrophage infiltration is under development.
Ferumoxytol (AMAG Pharmaceuticals, Lexington, MA), a superparamagnetic iron
oxide nanoparticle approved for treatment of iron deficiency anemia in patients
with chronic renal failure, is used as a contrast agent in MRI to track
macrophages[41]. It stays in vessels for up to 72 hours after
intravascular delivery, which is cleared by macrophages starting at 24 hours
after the delivery. Macrophages containing ferumoxytol can stay in tissues for
an extended period and thus allow delayed detection by MRI[42].
Since it is superparamagnetic, ferumoxytol is hypointense on T2*-weighted
images and hyperintense on T1-weighted images. These iron particles were first
used to detect inflammation in patients with aneurysm and then extrapolated to
patients with BAVMs[42,43]. Pilot studies co-localized T2* gradient
echo MR signal loss after ferumoxytol infusion with Prussian blue and CD68+
macrophages in the aneurysm domes and BAVM surgical specimens[44].
Thus, using ferumoxytol-enhanced MRI for assessing BAVM macrophage load is
feasible and can be developed as a potential biomarker to assess the risk of
BAVM rupture.
A crucial
finding regarding this new contrast in aneurysm is that the timing of
ferumoxytol uptake in aneurysm walls reflects aneurysm stability and predicts
the risk of rupture. Hasan et al[45] showed that all
aneurysms exhibit early uptake (24 hours after infusion) of ferumoxytol on MRI
ruptured in the next 6 months, whereas none of those with late uptake (72 hours
after infusion) ruptured during the follow-up period. Therefore, the early
signal change on MRI is thought to be associated with active inflammation and
increase of pro-inflammatory macrophages, hence indicating a greater risk of
hemorrhage. A further study demonstrated that ferumoxytol-enhanced MRI allows
assessment of the effects of anti-inflammatory pharmacological interventions on
cerebral aneurysm[46]. Although results are impressive, this method
has not been tested in BAVMs.
Imaging subtle
changes in BAVM may be challenging because of high-blood volume in the nidus[47].
Residual intravascular ferumoxytol signal interferes with the detection of iron
nanoparticles in the vascular wall or intervening stromal tissue. Delayed
imaging at 5 days after ferumoxytol infusion might be an optimal protocol for
BAVMs because it does not show as much of the intravascular tracer.
Although
current application of ferumoxytol-enhanced MRI in BAVM is limited, preliminary
data suggest that this new contrast MRI is a promising technique for detecting
macrophages and predicting BAVM rupture. Future studies will be needed to
develop reliable imaging biomarkers, similar to those in aneurysm studies, in
order to identify rupture-prone BAVMs, allowing relatively real-time
surveillance of the severity of intralesional inflammation and assessment of
the therapy.
Summary
The pathogenesis of BAVMs is complex and currently vague. Evidence
obtained from HHT BAVM models and analysis of human BAVM specimens suggests
that macrophages play a critical role in vascular integrity and vascular remodeling.
Figure 1 summarizes the potential roles and mechanisms of macrophages in BAVM
pathogenesis. Tracking macrophages is a promising and innovative method to
predict BAVM rupture.
Acknowledgment
This work was supported by grants to Hua Su from the National
Institutes of Health (R01 NS027713, R01 HL122774 and R21 NS083788) and from the
Michael Ryan Zodda Foundation and UCSF Research Evaluation and Allocation
Committee (REAC). Support was also provided by grants from the National Natural
Science Foundation of China (81271313) to Yuanli Zhao and Yi Guo, and from the
Hebei Provincial Natural Science Foundation of China (H2013201283) to Yi Guo.
We thank Voltaire Gungab for assistance with manuscript preparation.
CONFLICT OF INTERESTS
The authors have no conflicts of interest to declare.
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Peer reviewer: Yuri
V. Bobryshev, PhD, Senior Research Associate/Associate Professor, School of
Medical Sciences, Faculty of Medicine, University of New South Wales, NSW 2506
Kensington, Sydney, Australia.
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