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Journal of Stroke 2016;18(1):12-20
http://dx.doi.org/10.5853/jos.2015.01760
Special Review
The Pathophysiology of Moyamoya Disease:
An Update
a,d b c
Oh Young Bang, Miki Fujimura, Seung-Ki Kim
a
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
b
Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan
c
Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Korea
d
Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul, Korea
Moyamoya disease (MMD) is a unique cerebrovascular disease characterized by the progres- Correspondence: Oh Young Bang
sive stenosis of large intracranial arteries and a hazy network of basal collaterals called Department of Neurology, Samsung
moyamoya vessels. Because the etiology of MMD is unknown, its diagnosis is based on Medical Center, Sungkyunkwan
University, 81 Irwon-ro, Gangnam-gu,
characteristic angiographic findings. Re-vascularization techniques (e.g., bypass surgery) are Seoul 06351, Korea
used to restore perfusion, and are the primary treatment for MMD. There is no specific Tel: +82-2-3410-3599
Fax: +82-2-3410-1430
treatment to prevent MMD progression. This review summarizes the recent advances in E-mail: ohyoung.bang@samsung.com
MMD pathophysiology, including the genetic and circulating factors related to disease de- Received: December 13, 2015
velopment. Genetic and environmental factors may play important roles in the development Revised: December 25, 2015
of the vascular stenosis and aberrant angiogenesis in complex ways. These factors include Accepted: December 30, 2015
the related changes in circulating endothelial/smooth muscle progenitor cells, cytokines re- This study was supported by the Korean
lated to vascular remodeling and angiogenesis, and endothelium, such as caveolin which is Healthcare Technology R D Project,
&
Ministry of Health Welfare (HI14C1531).
a plasma membrane protein. With a better understanding of MMD pathophysiology, non- &
surgical approaches targeting MMD pathogenesis may be available to stop or slow the pro- The authors have no financial conflicts of
gression of this disease. The possible strategies include targeting growth factors, retinoic interest.
acid, caveolin-1, and stem cells.
Keywords Angiogenesis; Caveolin; Endothelial progenitor cells; Growth factors; Moyamoya
disease
Introduction subjective. In patients with MMD, the angiographic findings
can differ according to the progressive stage and age of presen-
Moyamoya disease (MMD) is a unique cerebrovascular tation, and the characteristic angiographic findings are not
1-3
disease characterized by the progressive stenosis of the distal consistently observed in all courses of MMD. In patients
internal carotid artery (ICA) and the resulting hazy network with an early stage of Suzuki’s angiographic grading, the ab-
4
of basal collaterals called moyamoya vessels. The etiology of normal vascular network is not yet evident. Unlike in child-
MMD is unknown. As a result, the criteria for the diagnosis of hood-onset MMD, the basal collaterals are often not promi-
3
MMD is based on characteristic angiographic findings. How- nent in adult-onset MMD. In addition, the patients may pres-
ever, the angiographic findings may not be sensitive or specific ent with unilateral MMD findings. In fact, the diagnostic cri-
to MMD. The current diagnostic criteria require the presence teria for definitive MMD was revised to include patients with
of prominent basal collaterals for the diagnosis of MMD. both a bilateral and unilateral presentation of the terminal
However, a decision on the presence of basal collaterals can be ICA stenosis with an abnormal vascular network at the base of
Copyright © 2016 Korean Stroke Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which
permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
pISSN: 2287-6391 eISSN: 2287-6405
12 http://j-stroke.org •
Vol. 18 / No. 1 / January 2016
the brain by the Research Committee of MMD of the Japa- These basal and cortical vessels may represent compensatory
nese Ministry of Health, Labour, and Welfare in 2015. mechanisms for the reduced cerebral blood flow or the aber-
Owing to the currently limited understanding of MMD, re- rant active neo-vascularization before the vascular occlusion.
vascularization techniques (e.g., bypass surgery) to restore An angiographic study of a large cohort of pediatric patients
perfusion are the primary treatment for MMD. There is no with MMD showed that the cortical neo-vascularization may
specific treatment to prevent MMD progression. The purpose occur before any significant hemodynamic impairment, sug-
of this review is to summarize the recent advances in MMD gesting that neo-vascularization is an active process, not a pas-
18
pathophysiology, including the genetic and circulating factors sive compensation for the vascular occlusion.
related to disease development. The complicated pathologic features of the stenotic seg-
ments of MMD (e.g., a coexistence of proliferation and shrink-
Pathological features of MMD age) and the unknown nature of the neo-vascularization (e.g.,
an aberrant vs. compensatory process) suggest that MMD
The main pathological changes of the stenotic segment in pathophysiology is a complex process.
MMD are the fibrocelluar thickening of the intima (e.g., the
hyper-proliferation of the vessel wall components, active an- Genetics underlying MMD
giogenesis, and matrix accumulation), irregular undulation of
the internal elastic laminae, medial thinness (e.g., an attenua- Approximately 10% of individuals with MMD exhibit a fa-
5-10
tion of media), and a decrease in the outer diameter. milial occurrence. Several genetic loci have been identified in
Recent neuroimaging techniques, such as the three-dimen- familial MMD, including 3p24-26,19 6q25,20 8q23,21 10q23.31,15
21 22
sional (3D) constructive interference in steady-state (CIISS) 12p12, and 17q25. In addition, MMD is also associated
magnetic resonance imaging (MRI) and high-resolution MRI with many genetically transmitted disorders, including neurofi-
studies of patients with MMD, have demonstrated a constric- bromatosis, Down syndrome, sickle cell anemia, and collagen
tive remodeling (e.g., the narrowing of the arterial outer diam- vascular disease. These findings suggest the importance of ge-
eter) in affected segments and a concentric enhancement of netic factors.
11-14
the symptomatic segments. In our data set from a large co-
hort of adult-onset MMD, most patients (90.6%) showed a RNF213 as a susceptible gene for MMD
long-segment concentric enhancement of the distal ICA and/ More recently, the Ring finger 213 (RNF213) gene in the
or middle cerebral artery on a high-resolution MRI, regardless 17q25-ter region was identified as the strongest susceptibility
of symptom presence or acuteness. The high-resolution MRI gene for MMD in East Asian people using a genome-wide
23,24
findings are consistent with the results of previous pathological linkage and exome analysis. The p.R4810K (c.14576G>A)
6,7
reports that showed intimal hyperplasia and medial thinness. variant of the RNF213 genetic variant was identified in 95% of
There is growing evidence that MMD is primarily a prolif- patients with familial MMD, 80% with sporadic MMD, and
23
erative disease of the intima. The smooth muscle proliferation 1.8% of control subjects in a Japanese population. The ho-
that is associated with an ACTA2 mutation has been postulat- mozygous p.R4810K variant of RNF213 predicted an early
25
ed to be the key mechanism of the vascular occlusion in famil- onset and severe form of MMD in both Japanese and Kore-
15 26
ial MMD. The histopathological findings in the distal ICA an patients with MMD. The population that is susceptible to
have shown a proliferation of the smooth muscle cells or en- MMD, such as carriers of the RNF213 p.R4810K variant, is
8,10,16 27
dothelium and a stenosis or occlusion associated with the estimated to be 16.16 million people in East Asian countries.
5
fibrocellular thickening of the intima. An enhancement of the The number of patients with MMD, which was conservatively
stenotic segments may represent either a neo-vascularization estimated at 1 per 300 carriers of the RNF213 p.R4810K vari-
27,28
or an intimal hyperplasia. ant, is considered to be 53,800 in East Asian populations.
The moyamoya vessels are the dilated perforating arteries Further genetic studies for MMD are warranted, particular-
that have various histopathological changes, including fibrin ly in populations outside East Asia, because the single nucleo-
deposits in the wall, fragmented elastic laminae, attenuated tide polymorphism (SNP) of p.R4828K in RNF213 is not the
5
media, and the formation of microaneurysms. In addition to susceptibility gene for MMD in Westerners or South Asian
the moyamoya vessels, cortical microvascularization, which is individuals. Novel variants in RNF213 in non-p.R4828K were
24
characterized by a substantially increased microvascular den- recently found in Caucasian and Chinese cases with MMD
17 29
sity and diameter, is suggested as a specific finding in MMD. and in the United States. For example, several variants of
http://dx.doi.org/10.5853/jos.2015.01760 http://j-stroke.org
13
Bang, et al.
Pathophysiology of Moyamoya Disease
RNF213 in non-p.R4810K (i.e., rs148731719, rs397514563) sponse to inflammatory signals from the environment. How-
were recently found in Caucasian and East and South Asian ever, further studies are needed to elucidate the differential
patients with MMD.24,29-31 In addition, the clinical manifesta- pathological processes between the endothelium (e.g., low-
tions and possibly angiographic findings may differ between ered angiogenesis) and smooth muscle cells (e.g., abnormal
Westerners and East Asians.32 The p.R4810K RNF213 variant proliferation that causes moyamoya vessel formation and ste-
was reportedly related to the ischemic type of MMD, while nosis of the major intracranial arteries).
the non-p.R4810K RNF213 variants, particularly A4399T, In addition to the preclinical data, clinical data has also
30
were associated with the hemorrhagic-type of MMD. shown that exposure to environmental factors, such as an au-
toimmune response and infection/inflammation, in MMD-
Function of RNF213 on MMD pathophysiology susceptible subjects may be associated with the angiographic
35
The exact function of RNF213 is unknown. Recent in vivo features of MMD. For example, autoimmune thyroid disease
experiments using genetically engineered RNF213 mice ad- has been reported in different MMD populations (i.e., pediat-
dressed the mechanism underlying the RNF213 SNPs in the ric and adult-onset MMD, East Asians, and Westerners) and
40-42
development of MMD pathology. The target disruption of may be involved in MMD development. In addition, the
RNF213 did not induce MMD in the RNF213-defcient mice RNF213 genetic variant may be associated with vascular risk
33 43
under normal conditions. Kanoke and colleagues alterna- factors, such as hypertension, and also could lead to vascular
tively generated RNF213-knock-in mice that expressed a mis- fragility, which may make vessels more vulnerable to hemody-
sense mutation in the mouse RNF213, p.R4828K, on Exon namic stress and secondary insults.35
61, which corresponds to the human RNF213, p.R4859K, on
Exon 60 in MMD patients; however, these mice did not de- Polymorphisms of microRNAs
34
velop MMD under normal conditions. These negative re- MicroRNAs (miRs), which are small non-coding RNAs
sults could be consistent with the low penetrance rate of the (~23 nucleopeptides), negatively regulate the expression of
RNF213 polymorphisms in patients with MMD, and may in- many proteins by altering their gene expression through post-
dicate the importance of environmental factors in addition to transcriptional repression or mRNA degradation.44 miRs may
35
the genetic factors. They subjected the RNF213-deficient play an essential role in the regulation of proliferation, differ-
mice to an ischemic insult, and found that the post-ischemic entiation, survival, and aging of various tissues and cells, in-
angiogenesis was significantly enhanced in the mice lacking cluding stem cells. There is increasing evidence that miRs that
36
RNF213 after a chronic hindlimb ischemia. This suggests are altered after focal ischemia have a functional significance
the potential role of a RNF213 abnormality in the develop- in the recovery after stroke as well as ischemic pathophysiolo-
ment of abnormal vascular networks in chronic ischemia. gy. Preclinical studies of ischemic stroke have demonstrated
Hitomi et al. established a model of induced pluripotent that miRs protect against focal ischemia and reperfusion inju-
stem cells derived from vascular endothelial cells (iPSECs), ry by inhibiting oxidative stress.45 They are also involved in in-
46-48
and showed that the angiogenic activity from patients with flammation, neurogenesis, and angiogenesis.
MMD and RNF213 carriers was lower than that of the control A genome-wide miR array analysis of the serum from pa-
subjects. The overexpression of the RNF213 variant down- tients with MMD showed elevated serum levels of miRs asso-
37
regulated Securin and inhibited angiogenic activity. They ciated with RNF213 and BRCC3 (i.e., BRCA1/BRCA2-con-
also showed that RNF213 may be a mediator downstream of taining complex, an important angiogenesis-related protein),
49
the IFN-β signaling pathway in endothelial cells. Carriers of both of which are involved in MMD pathogenesis. In addi-
the RNF213 variant may be susceptible to cerebral hypoxia tion, a SNP of miR-196a was associated with MMD.50 ANXA1,
51
because of insufficient angiogenesis if inflammation and hy- which is expressed in endothelial and smooth muscle cells, is
38
poxia occur simultaneously. Ohkubo and colleagues also a gene target of miR196a and mediates the apoptosis and inhi-
52
showed that pro-inflammatory cytokines activated RNF213 bition of cell proliferation.
transcription, and RNF213 functions as a common down-
stream effector of the PI3 kinase-AKT pathway in endothelial Biomarkers underlying vascular stenosis
39
angiogenesis. These data suggest that although MMD is not and aberrant angiogenesis
an inflammatory disease, inflammation may play an important
role in MMD development. RNF213 plays a unique role in In addition to genetic biomarkers, there are circulating fac-
endothelial cells regarding the proper gene expression in re- tors that may be involved in MMD pathogenesis, including cir-
14 http://j-stroke.org http://dx.doi.org/10.5853/jos.2015.01760
Vol. 18 / No. 1 / January 2016
culating endothelial progenitor cells (EPCs), cytokines, and binding protein-1 (CRABP-1), and (c) cytokines related to in-
55,60-64
caveolin. flammation. The investigations regarding the role of these
factors have been inconclusive.
Circulating vascular progenitor cells A genetic study of familial MMD investigated the balance
In patients with acute myocardial infarcts or ischemic stroke, between MMPs and their inhibitors, and found that the pres-
increasing evidence points to a role for circulating EPCs that ence of a certain MMP inhibitor genotype may be a predis-
65
originate from the bone marrow and help maintain the vascu- posing genetic factor for familial MMD. The levels of several
lature and blood flow in an infarcted area.53 EPCs potentially trophic factors, such as VEGF, basic fibroblast growth factor,
contribute to the neo-vascularization at the ischemic brain in- and PDGF-BB, were increased, but the VEGF receptor levels
54 60,66,67
jury site in patients with MMD. Rafat et al. reported the pres- were decreased in MMD compared to that of controls. In
ence of increased levels of circulating EPCs in patients with addition, certain VEGF polymorphisms were associated with
55 68
MMD. In contrast, Kim et al. demonstrated decreased EPC pediatric MMD and poor collateral vessel formation. How-
levels and defective angiogenic function in EPCs in pediatric ever, these findings were not observed in other studies.69 Us-
patients with MMD, indicating there is abnormal angiogenesis ing a multifactor dimensionality reduction method, a recent
during MMD pathogenesis.56 Similarly, impaired EPC func- study evaluated the interactions of different loci for MMD,
57
tion was observed in adult patients with MMD. Recently, Lee but failed to show any influence of β-type PDGF receptor and
et al. reported a downregulation of retinaldehyde dehydroge- MMPs on MMD.69 Young et al. suggested that the induction
nase 2 (RALDH2) using the gene expression profiles of EPC of pro-inflammation cascades and VEGF expression is sec-
in pediatric patients with MMD. The epigenetic suppression ondary to the infarct rather than part of the primary MMD
70
of RALDH2 expression contributed to the defective function pathology.
of MMD endothelial colony-forming cells; this could be res- Changes in the levels of these factors may be simply associ-
58
cued by supplying retinoic acid in vitro and in vivo. Aberrant ated with the disease rather than causative, as many of these
angiogenesis was an active angiogenetic process that may cause factors are also increased in patients with stroke. However,
both stenosis through the proliferation of endothelial and/or Kim and colleagues identified a polypeptide spot, CRABP-1,
8
smooth muscle cells and abnormal collateral formation. in cerebrospinal fluid from pediatric patients with MMD us-
In addition to endothelial cells, the smooth muscle cells are ing a proteomics analysis.63 A higher CRABP-1 level in the
also involved in this disease process. The MMD pathology is CSF was associated with a typical bilateral involvement and a
characterized by smooth muscle cell hyperplasia in the intima. decrease in the basal collaterals post-operatively in adult
71
Mutations in the smooth muscle cells, such as smooth muscle MMD. It has been proposed that the retinoids attenuate
alpha-actin, which is encoded by ACTA2, may be involved in growth factor-stimulated smooth muscle cell migration and
the increased proliferation of the smooth muscle cells, contrib- proliferation, and CRABP-1 can negatively regulate retinoic
15 63
uting to occlusive diseases. Recently, Kang and colleagues acid activity. These findings suggest an important role for
cultured and isolated smooth muscle progenitor cells (SPCs) retinoid signaling in MMD pathogenesis by controlling the
from the peripheral blood of patients with MMD, and showed growth factor expression.63 Further studies are needed to de-
that the SPCs in the MMD group tended to make more irregu- termine whether retinoids are efficacious for MMD treatment.
larly arranged and thickened tubules, as well as express differ- Although pathological analyses have revealed that the af-
59
ential genes compared to that of the healthy controls. These fected vessels do not show any inflammatory changes that lead
16
findings suggest a defect in the cell maturation process that to occlusion, the role of inflammation in the fibrocellular
might have occurred in the SPCs from the patients with MMD. thickening of the intima and the disease pathogenesis are also
being investigated. The plasma levels of MMPs, monocyte
Cytokine and their polymorphisms chemoattractant protein-1, and inflammatory cytokines (in-
Various cytokines and their polymorphisms are associated terleukin-1b) were higher in patients with MMD compared to
60 72
with MMD, including (a) growth factors, such as vascular en- those in controls. A previous study, as well as our unpub-
dothelial growth factor (VEGF), fibroblast growth factor, lished data, showed that the levels of E-selectin, which is in-
platelet-derived growth factor (PDGF), and hepatocyte growth volved in endothelial progenitor cell recruitment and angio-
factor, (b) cytokines related to vascular remodeling and angio- genesis) were increased in both patients with MMD and those
genesis, such as matrix metalloproteinases (MMPs) and their with atherosclerotic stroke.
inhibitors, hypoxia-inducible factor-1α, and cellular retinoic
http://dx.doi.org/10.5853/jos.2015.01760 http://j-stroke.org
15
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