Experimental animal models for the study of moyamoya disease

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  • 1 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland;
  • | 2 Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia; and
  • | 3 Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
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Moyamoya disease is a rare disorder of the cerebrovascular system affecting individuals in a bimodal age distribution and is characterized by progressive vascular stenosis of the bilateral supraclinoid internal carotid arteries with compensatory formation of collateral vessels at the base of the brain. Despite the disease’s initial description in the literature in 1957, little progress has been made in the development of medical and surgical therapeutics due to, in no small part, the lack of effective experimental animal models. Currently, there is a poor understanding of the pathophysiological mechanisms behind the development of the moyamoya vasculopathies. Since the description of a genetic association between moyamoya disease, few studies have investigated the impact of genetic manipulation on the development of an animal model for experimentation. To date, no one model recapitulates the precise phenotype of the moyamoya vasculopathies, although development of an appropriate model would allow for an in-depth investigation into the pathological mechanisms underlying the disease. In this review, the authors discuss the immunological, mechanical, and genetic methods used to develop moyamoya experimental models, as well as future perspectives.

ABBREVIATIONS

ACA = anterior cerebral artery; CCA = common carotid artery; CCH = chronic cerebral hypoperfusion; EPC = endothelial progenitor cell; ICA = internal carotid artery; ICAS = ICA stenosis; LGA-50 = lactic acid–glycolic acid copolymer; MCA = middle cerebral artery; MDP = muramyl dipeptide; MMD = moyamoya disease; MMP-9 = matrix metalloproteinase-9; MMS = moyamoya syndrome; RNF213 = ring finger protein 213; SMPC = smooth muscle progenitor cell; tMCAO = transient MCA occlusion.

Moyamoya disease is a rare disorder of the cerebrovascular system affecting individuals in a bimodal age distribution and is characterized by progressive vascular stenosis of the bilateral supraclinoid internal carotid arteries with compensatory formation of collateral vessels at the base of the brain. Despite the disease’s initial description in the literature in 1957, little progress has been made in the development of medical and surgical therapeutics due to, in no small part, the lack of effective experimental animal models. Currently, there is a poor understanding of the pathophysiological mechanisms behind the development of the moyamoya vasculopathies. Since the description of a genetic association between moyamoya disease, few studies have investigated the impact of genetic manipulation on the development of an animal model for experimentation. To date, no one model recapitulates the precise phenotype of the moyamoya vasculopathies, although development of an appropriate model would allow for an in-depth investigation into the pathological mechanisms underlying the disease. In this review, the authors discuss the immunological, mechanical, and genetic methods used to develop moyamoya experimental models, as well as future perspectives.

ABBREVIATIONS

ACA = anterior cerebral artery; CCA = common carotid artery; CCH = chronic cerebral hypoperfusion; EPC = endothelial progenitor cell; ICA = internal carotid artery; ICAS = ICA stenosis; LGA-50 = lactic acid–glycolic acid copolymer; MCA = middle cerebral artery; MDP = muramyl dipeptide; MMD = moyamoya disease; MMP-9 = matrix metalloproteinase-9; MMS = moyamoya syndrome; RNF213 = ring finger protein 213; SMPC = smooth muscle progenitor cell; tMCAO = transient MCA occlusion.

Initially described in Japan in 1957, moyamoya disease (MMD) is a rare disorder of the cerebral vasculature characterized by progressive vascular occlusion affecting the supraclinoid portion of the internal carotid arteries (ICAs) with compensatory formation of an abnormal reticular vascular profile at the base of the brain.1–4 Moyamoya, termed due to similarities between the abnormal vascular network and the Japanese description of a “puff of smoke,” is a general term that describes two distinct conditions affecting the intracranial ICA: MMD and moyamoya syndrome (MMS).1 Unlike MMS, MMD has been well characterized, and its incidence ranges between 0.94 and 2.3 cases per 100,000 individuals in East Asia. However, it drops to 0.09/100,000 individuals in North America.5 MMS is a moyamoya-like vasculopathy with associations with Down syndrome, thyroid disease, cranial irradiation, or a variety of other comorbid conditions.6 Unlike MMD, MMS is not associated with genetic or familial inheritance.7 Although different terms are used to describe the conditions, the anatomical and clinical features of MMD and MMS are remarkably similar, often leading to the theory that the associated comorbid conditions are predisposing conditions, rather than causative in nature.8 Regardless, substantial effort has gone into understanding the pathophysiology, etiology, and clinical features of moyamoya vasculopathies, both the disease and the syndromic subtypes, despite their rarity.

While the pathophysiological mechanism behind MMD development is still unclear, advances in understanding the histopathological and genetic associations with MMD have been made in the last 2 decades. Histologically, MMD is characterized by noninflammatory intimal thickening of the bilateral ICAs.9 The occlusive lesions bear histological resemblance to atherosclerotic lesions with endothelial injury, intimal hyperplasia, and smooth muscle cell proliferation. Due to the reduced cerebral blood flow, a collateral network of blood vessels develops at the base of the brain, termed “moyamoya vessels.” However, from a histopathological perspective, in contrast to the appearance of the ICAs, the moyamoya collaterals do not exhibit the same inflammatory cellular components and, rather, exhibit features of accelerated vascular remodeling.10–13 Through familial analysis, the ring finger protein 213 (RNF213) gene located in the 17q25.3 region has been implicated in the pathogenesis of MMD, along with a variety of occlusive cerebrovascular diseases, and atherosclerotic intracranial major artery stenoses and occlusions.14,15

Although strides have been made in understanding the pathophysiological mechanisms underlying MMD, the combination of disease heterogeneity and lack of animal models has led to stagnation in understanding the disease. An ideal MMD animal model would effectively replicate both the gradual, progressive vascular occlusion and the development of collateral basal vessels.2 A variety of methods have been developed in attempt to produce an effective MMD model, including mechanical occlusion or stenosis at various points within the cerebral vasculature, immune-mediated arterial injury, and genetic mechanisms.3,9,10,16–18 In this review, we will discuss the current state of experimental animal models for MMD and highlight potential directions for future work.

Immunological Techniques for Moyamoya Model Development

Prior to the discovery of the genetic associations of MMD, early observations suggested that MMD may be a form of vasculitis with a predilection for the cerebral vasculature.3,10 Furthermore, a variety of early research indicated abnormal thrombogenesis and immune complex deposition within the vasculature of affected patients, ultimately lending to an “inflammatory and immunological” etiological proposition.9,19 In light of this theory, in 1992, Ezura et al. attempted to induce an MMD model in rabbits by implementing a serum sickness vasculitis model combined with intracisternal administration of antibodies or antigens.3 Rabbits were injected with heterologous serum via a combination of intravenous and intracisternal routes before being euthanized for analysis. Interestingly, rabbits that were exposed to only intravenous heterologous serum did not develop any features of cerebral arteritis. However, any rabbit exposed to intracisternal heterologous serum, regardless of intravenous exposure, exhibited transient features of cerebral arteritis with significant periarterial inflammatory cell infiltrate. These histopathological markers of arteritis were not present after 3 days and likely represented a transient local immune reaction to the intracisternal antigen deposition.

In 2003, Kamata et al. attempted to induce MMD in a feline model through a combined immunological-embolic method utilizing rod-shaped lactic acid–glycolic acid copolymer (LGA-50) and muramyl dipeptide (MDP) injected unilaterally into the ICA.9 This technique was successful in inducing an MDP-dependent immunological reaction within the intimal layer of the ICA. Similar to histological analysis of MMD-affected patients, the affected feline ICAs demonstrated mild intimal thickening with corresponding duplication of the internal elastic lamina within the terminal portions of the ICA, anterior cerebral artery (ACA), and middle cerebral artery (MCA). Interestingly, despite injection of the immuno-embolic agent unilaterally, histological changes of the intimal layers were present in the bilateral ICAs and its downstream tributaries. However, although a subset of the histological characteristics was replicated in the feline model, the development of moyamoya vessels at the base of the brain was not demonstrated with this technique. This may have been due to the difference in feline cerebral vasculature compared with human cerebral vasculature; feline brains receive a rich vascular supply from the external carotid artery. Therefore, the feline model did not exhibit severe cerebral hypoperfusion secondary to the unilateral ICA occlusion produced through this experimental technique.

In 2003, Terai et al. also utilized MDP to develop an experimental model for MMD in monkeys, which have a carotid artery system that is morphologically similar to that of humans.20 Lamination and reduplication of the internal elastic lamina of the intracranial arteries was seen, but neither stenosis of the carotid arteries nor development of collateral basal vasculature was observed. Although a number of groups have attempted to induce MMD in canine, monkey, and rat models after the study of Kamata et al., none were successful in replicating the full phenotype of MMD, and efforts since then have shifted in favor of mechanical and genetic methods of induction.3,20–22

Mechanical Techniques for Moyamoya Model Development

As patients with MMD exhibit features of chronic cerebral hypoperfusion (CCH), one of the most common methods of creating an experimental MMD animal model is through occlusion or stenosis of the common carotid arteries (CCAs) and ICAs at various points.13,23–26 Similar to other cognitive and vascular disorders, cerebral perfusion in MMD is diminished, and a variety of techniques have been developed both to recreate these hypoperfused states in animal models and to grade and treat patients with CCH. Given the underlying pathophysiological similarity between chronic vascular cognitive diseases and MMD, the experimental techniques have been adopted for use in MMD.14 A number of techniques have been developed to recreate this chronic hypoperfused state including bilateral CCA occlusion/stenosis in rats (also known as 2-vessel occlusion/stenosis), gradual bilateral CCA occlusion, and a 4-vessel occlusion model.27–31

An important consideration in the development of a CCH animal model is the tolerance to ischemic injury. The C57BL/6 mouse, a common experimental model, is extremely susceptible to cerebral ischemia and has demonstrated a high mortality rate following bilateral carotid artery occlusion, as demonstrated in 1997 by Yang et al.32 Furthermore, as a species, mice are more susceptible to ischemic injury and exhibit neuronal death within 30 minutes compared with the 60 to 120 minutes required to induce cell death in rats.33,34 From an anatomical perspective, a number of transgenic mice exhibit varying cerebrovascular organization and lack communicating arteries within the circle of Willis, severely reducing the animal’s tolerance to infarcts.32,35 Despite the limitations of these animal models, they play a crucial role in the understanding of MMD, and many methods of inducing CCH have been trialed to date.

Carotid artery occlusion or stenosis remains the most common method of inducing CCH in rodents; however, it is important to note that a majority of these trials were conducted in the context of chronic vascular cognitive disease such as Alzheimer’s disease or cerebral small vessel disease.16,23,26,36,37 Shibata et al. were able to successfully induce CCH in C57BL/6 mice through bilateral carotid artery stenosis using 0.18-mm-inner-diameter microcoils.36 Importantly, this model exhibited features of preserved gray matter structures and visual pathways due to maintenance of residual blood flow in the carotids and tributaries.

A factor complicating the development of an occlusion model is the abrupt interruption in blood flow when the carotid arteries are uni- or bilaterally occluded.13,23 A recent technique pioneered by Wang et al.23 in 2020, implemented a bilateral carotid artery stenotic mechanism in Wistar rats and demonstrated superior cognitive, vascular, and technical results in comparison with rats who underwent a bilateral carotid artery occlusion procedure. Importantly, cerebral blood flow remained persistently lower in the treatment groups in comparison with the control group for 14 days. While this model was developed with the goal of inducing a vascular cognitive impairment model, the reliable vascular reduction obtained in this study may prove promising for further studies evaluating this technique in the induction of an MMD model.23

Unfortunately, since many of these models have been developed for the purpose of vascular cognitive impairment replication, the histological and pathological vascular profiles of these models do not fit those of MMD precisely. MMS has a relatively similar anatomical profile to MMD; however, it is not associated with any genetic alterations. Because of this, in 2018 Roberts et al. developed a novel surgical model, termed internal carotid artery stenosis (ICAS) for MMS by placing microcoils in the proximal ICA in C57BL/6 mice.2 Following ICAS, decreased vessel diameter was observed in the ipsilateral ICA and ACA compared with the control mice. Of note, the experimental model was successful in mimicking the moyamoya-like vasculopathy seen in Suzuki stage I MMD. Although this study was conducted as an exploratory study with few animals and within a short timeframe, it provides the first experimental animal model created through surgical interventions specific for moyamoya vasculopathies.

Genetic Techniques for Moyamoya Model Development

The RNF213 gene, also known as the MMD susceptibility gene, encodes the ring finger domain, which, through E3 ubiquitin-protein ligase activity, modulates protein levels within mammalian tissues.38 By assisting the transfer of ubiquitin to a variety of heterologous substrates, RNF213 ultimately plays a crucial role in the regulation of cellular survival or death.14,38 Through familial whole genome analyses, a founder missense mutation in RNF213, p.R4859 K, was found to be tightly associated with the development of MMD (OR 190.8, 95% CI 71.7–507.9).39 Its role in the pathogenesis of MMD has been a topic of interest, and recent studies have demonstrated an upregulation of the RNF213 gene in response to cerebral ischemia.14 In conditions of concurrent hypoxia and inflammation, commonly seen in patients with MMD, RNF213 mutations may predispose individuals to increased susceptibility to cerebral hypoxia secondary to aberrant and insufficient angiogenesis.18 In an effort to develop an experimental model through manipulation of the RNF213 gene, a number of studies have been conducted in a variety of animals; however, a paucity of information remains.

Initially established in zebrafish, two RNF213 genes, RNF213-a and RNF213-b, which produce amino acid sequences that are human RNF213 orthologs, were identified by Liu et al.10 Subsequently, RNF213 knockdown zebrafish were produced and exhibited abnormal vascular development in the head, but relatively normal vasculature in the trunk. In a similar manner to the abnormal basal vasculature seen in MMD, knockdown zebrafish specifically developed multiple aberrant vessels with irregular diameters originating from the inner optic circle and connecting to cranial vessels. This abnormal vascular development, specifically in the cranial regions, suggests that RNF213 plays a crucial, selective role in intracranial angiogenesis.

Given the promising results demonstrated in zebrafish, attempts at creating a murine MMD model through RNF213 knockdown were attempted by Sonobe et al. in 2014.17 Through deletion of exon 32 of RNF213 using the Cre-lox system, homozygous knockout C57BL/6 mice were generated and observed. All knockout mice were observed for 64 weeks until they were euthanized, and radiological and histopathological analyses were conducted. In contrast to the effect of RNF213 knockdown in zebrafish, radiological evaluation through MRA of RNF213 knockout mice did not reveal any gross malformations in the circle of Willis development, leptomeningeal anastomoses, or significant difference in vascular wall thickness compared with wild-type mice. However, RNF213 knockout mice that also underwent CCA ligation demonstrated significantly thinner intimal and medial layers compared with wild-type mice. In a corroborating study with RNF213 knock-in mice, Kanoke et al. found no significant difference in circle of Willis anatomy or MRA findings.40 Ultimately, in contrast to knockdown zebrafish, RNF213 knockout was not sufficient to induce MMD in mice, but additional mechanical stress may be necessary to induce an accurate MMD model.17,40

In a follow-up study to clarify the role of RNF213 knockout in inducing MMD, Sonobe et al. investigated the role of matrix metalloproteinase-9 (MMP-9) in RNF213 knockout mice following CCA ligation.41 RNF213 knockout mice demonstrated higher levels of MMP-9 and thinner vascular walls compared with wild-type mice, suggesting that the combination of insults may reflect early characteristic changes seen in MMD. From a cellular physiological standpoint, MMP-9 may be elevated in the knockout mice due both to an increase in reactive oxygen species secondary to local ischemia following CCA ligation and also from local immunological interactions between the affected vascular wall and blood cells.41–43

The concept that an RNF213 mutation alone may not be sufficient to promote or induce MMD has led to discussion of various factors, such as local inflammatory factors, playing a role in the development of this disease.44 Vascular endothelial progenitor cells (EPCs) are crucial to the maintenance of the vascular bed by producing proangiogenic factors that not only promote survival of surrounding endothelial cells, but also assist in the function of smooth muscle progenitor cells (SMPCs). In MMD, immunohistochemical findings indicate both proliferation of endothelial cells and smooth muscle cells in the distal ICA, lending to the theory that the role of EPCs may be more involved than is currently understood.4,11,44 From a number of in vitro studies, EPCs have demonstrated impaired angiogenic potential in MMD and, therefore, are a potential target for in vitro model development.45 With regard to SMPCs derived from patients with MMD, Kang et al. demonstrated their aberrant activity in cell culture with abnormal gene expression and development of irregularly arranged and thickened tubes in cell culture.46 Due to the paucity of information regarding the biology of EPCs and SMPCs, a deeper understanding of the aberrant progenitor cells is necessary prior to the development of more accurate genetically produced MMD in vivo or in vitro experimental models.22

Of note, the RNF213 knockout model has shown promise regarding development of the pathologic moyamoya vessels. In 2015, Ito et al. observed increased systemic angiogenesis in C57BL/6 RNF213 knockout mice following hind-limb ischemia.1 The authors were unable to identify a mechanism to explain this feature but speculated that given the increased MMP-9 concentrations found in patients with MMD, their murine model may have been exhibiting features of an MMP-9–independent proangiogenic pathway.1,47,48 Given the lack of an ideal MMD model that replicates both cerebral hypoperfusion along with angiogenesis at the base of the brain, Ito et al. implemented a transient middle cerebral artery occlusion (tMCAO) model that is frequently used to model ischemic strokes. No difference in cerebral angiogenesis was observed between the wild-type and RNF213 mice. This may be due to the acute nature of the tMCAO model in contrast to the chronic nature of moyamoya vasculopathies.1 Ultimately, although the mechanism behind the moyamoya vessel development is still largely unknown, the observed increase in angiogenic potential of an in vivo rodent model allows for future studies evaluating the underlying pathophysiological mechanisms.

Discussion

The role of experimental animal models in the understanding of MMD cannot be overstated. Unfortunately, the limited availability of quality moyamoya models produces many challenges to the understanding of the pathophysiology behind the disease and, ultimately, to developing novel treatments for patients with MMD. Initial efforts to develop a model through immunological manipulation, unfortunately, did not result in an appropriate model but did lead to increased understanding of the disease, allowing for the development of more effective methods (Fig. 1).

FIG. 1.
FIG. 1.

Illustration of the representative technical methods for the induction of MMD in murine models. A: Technical methods for the mechanical induction of MMD with the use of an aneurysm clip to produce complete occlusion (1) and the use of incomplete ligature to induce variable degrees of stenosis of the unilateral or bilateral CCAs (2). B: The genetic methods of RNF213 gene knockdown or knockout in combination with mechanical obstruction in murine models. C: The immunological methods of MMD with an illustrative example of the ICA administration location. Made in BioRender (biorender.com).

Animal models function as a translational facet for understanding the disease while acting as a segue for the development of various therapeutic agents. Through the development of genetic MMD models, recent studies have demonstrated the role of RNF213 not only in MMD but also in the pathogenesis of various systemic vasculopathies within the pulmonary and cardiac vasculature.49 This not only allows for improved treatment of these systemic vasculopathies but also aids in the development of genetic therapeutics targeted at correcting RNF213 mutations.50 As described previously, the development of MMS has been associated with the presence of autoimmune disease; however, the exact association between the two entities is not well understood. Using the ICAS model pioneered by Roberts et al., the combination of such models with a transgenic mouse that expresses autoimmune disease could provide a model to understand both the disease progression and potential treatment modalities for moyamoya vasculopathies.2

From a surgical standpoint, current techniques focus on direct and indirect revascularization modalities, although both have ideal patient populations.5 A recent meta-analysis revealed the superiority of direct revascularization over indirect methods in regard to stroke risk; however, the most common complication following direct revascularization is hyperperfusion syndrome secondary to the increased cerebral blood flow.51 Management of hyperperfusion syndrome is characterized by adequate blood pressure and cerebral edema control; development of an adequate animal model would be invaluable for the experimentation of various operative methods.5 Indirect revascularization relies on the angiogenic potential of the grafted tissue. As discussed by Yu et al., understanding the biology of EPCs is crucial in improving the efficacy of indirect vascularized grafts.44

There are a number of steps that could be implemented by the moyamoya research community that would aid in the development of an ideal experimental animal model. Standardizing the animal model development protocol would allow for more rapid progress. The Animal Research: Reporting In Vivo Experiments (ARRIVE) guidelines outline the “essential 10” items that aid researchers in improving the standards of animal model development from design conception through publication.52 A key feature lacking in prior moyamoya animal model studies is the randomization of animals exposed to the experimental group along with a blinded assessment of outcomes. When assessing for induction of moyamoya gross and histological characteristics, it is imperative that the assessing researcher is blinded to ensure reproducibility by subsequent investigators. Additionally, while some negative results have been reported in the literature regarding moyamoya experimental models, improved publication of these trials along with their methodologies would help guide future research in this field. Clinically, neurovascular imaging plays a central role in the diagnosis and treatment of MMD in humans. A more robust investigation of imaging techniques in preclinical models may be instrumental in assessing the success of a novel animal model along with the radiological features of human MMD. Finally, from a basic science perspective, additional research in both the genetic and cellular biological fields would greatly enhance the limited understanding of the pathology underlying MMD.

As described in this review, a number of methods have been investigated in the development of an MMD model. Significant strides have since been made, and recent work has produced models that resemble moyamoya vasculopathies through surgical and genetic means, although neither method alone produces a perfect moyamoya replica. The development of the ICAS model in 2018 provides an easily replicable and implementable option for producing the cerebral hypoperfusion observed in patients with MMD. However, in the short study period, the ICAS model was unable to demonstrate the development of moyamoya vessels.2 Promising results for the development of the characteristic moyamoya vessels were seen in RNF213 knockout mice that exhibited increased systemic angiogenesis following exposure to transient hindlimb ischemia (Table 1).1,17,40,41 While we acknowledge the significant paucity of information within this realm, future work to combine the surgical and genetic approaches may be worthwhile to examine the effect of CCH in RNF213 knockout mice. The lack of information regarding the development of additional medical and surgical modalities highlights the need for a rapid increase in the number of preclinical and translational studies evaluating the biology of MMD.

TABLE 1.

Overview of experimental moyamoya animal models

Authors & YearInducement TechniqueAnimalHistological/Pathological ChangesCerebral HypoperfusionMoyamoya Vessels
Ezura et al., 19923Intraventricular serum sicknessRabbitPeriarterial inflammatory cell infiltrateNoNo
Kamata et al., 20039Unilat ICA injection of LGA-50 & MDPCatIntimal thickening & duplication of internal elastic lamina in bilat terminal ICA, ACA, & MCANoNo
Terai et al., 200320MDP onlyMonkeyLamination & duplication of internal elastic lamina w/o carotid artery stenosisNoNo
Wang et al., 202023; Washida et al., 201930; Yang et al., 199732; Farkas et al., 200727BCAOC57BL/6 mouseNeuronal death secondary to ischemic brain injury, high mortalityYesNo
Wang et al., 202023; Shibata et al., 200436BCASC57BL/6 mouse & Wistar ratPersistent cerebral blood flow reductionYesNo
Roberts et al., 20182ICASC57BL/6 mouseDecreased vessel diameter, Suzuki stage IYesNo
Liu et al., 201110RNF213 knockdownZebrafishAbnormal cranial vascular developmentNoYes
Sonobe et al., 201417RNF213 knockoutC57BL/6 mouseNoneNoNo
Ito et al., 20151; Sonobe et al., 201417; Kanoke et al., 201540RNF213 knockout & CCA ligationC57BL/6 mouseThinned intimal & medial layers & increased systemic angiogenesisYesYes

BCAO = bilateral carotid artery occlusion; BCAS = bilateral carotid artery stenosis.

Conclusions

Ultimately, the limited availability of a moyamoya experimental animal model has stagnated and prevented the development of improved therapeutic options for patients with MMD. While the genetic method of producing an RNF213 knockout in mice has demonstrated positive results from the perspective of replicating the increased aberrant angiogenesis and histopathological changes seen in MMD, it is not yet capable of inducing the development of moyamoya vessels at the base of the brain. Similarly, surgical methods of reducing cerebral blood flow have shown promise in the replication of the cerebral hypoperfusion seen in MMD and also in reproducing the early pathological changes of the ICA seen in moyamoya patients. Despite their promising results, both aspects of MMD inducement have been sparsely tested and have been conducted as pilot studies. Further experimentation into the development of an adequate model is long overdue and would provide an invaluable resource for understanding MMD and the moyamoya vasculopathies, along with developing novel medical and surgical treatment options.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Ampie, Letchuman. Acquisition of data: Letchuman. Analysis and interpretation of data: Ampie, Letchuman, Mastorakos, Park. Drafting the article: Ampie, Letchuman, Mastorakos. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ampie. Study supervision: Raper, Kellogg, Park.

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    • Export Citation
  • 26

    Duncombe J, Kitamura A, Hase Y, Ihara M, Kalaria RN, Horsburgh K. Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia. Clin Sci (Lond). 2017;131(19):24512468.

    • Search Google Scholar
    • Export Citation
  • 27

    Farkas E, Luiten PGM, Bari F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Brain Res Rev. 2007;54(1):162180.

    • Search Google Scholar
    • Export Citation
  • 28

    Jing Z, Shi C, Zhu L, Xiang Y, Chen P, Xiong Z, et al. Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment. J Cereb Blood Flow Metab. 2015;35(8):12491259.

    • Search Google Scholar
    • Export Citation
  • 29

    Ihara M, Taguchi A, Maki T, Washida K, Tomimoto H. A mouse model of chronic cerebral hypoperfusion characterizing features of vascular cognitive impairment. Methods Mol Biol. 2014;1135:95102.

    • Search Google Scholar
    • Export Citation
  • 30

    Washida K, Hattori Y, Ihara M. Animal models of chronic cerebral hypoperfusion: from mouse to primate. Int J Mol Sci. 2019;20(24):6176.

  • 31

    Yang Y, Kimura-Ohba S, Thompson J, Rosenberg GA. Rodent models of vascular cognitive impairment. Transl Stroke Res. 2016;7(5):407414.

    • Search Google Scholar
    • Export Citation
  • 32

    Yang G, Kitagawa K, Matsushita K, Mabuchi T, Yagita Y, Yanagihara T, Matsumoto M. C57BL/6 strain is most susceptible to cerebral ischemia following bilateral common carotid occlusion among seven mouse strains: selective neuronal death in the murine transient forebrain ischemia. Brain Res. 1997;752(1-2):209218.

    • Search Google Scholar
    • Export Citation
  • 33

    Carmichael ST. Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx. 2005;2(3):396409.

  • 34

    Canazza A, Minati L, Boffano C, Parati E, Binks S. Experimental models of brain ischemia: a review of techniques, magnetic resonance imaging, and investigational cell-based therapies. Front Neurol. 2014;5:19.

    • Search Google Scholar
    • Export Citation
  • 35

    Wellons JC III, Sheng H, Laskowitz DT, Mackensen GB, Pearlstein RD, Warner DS. A comparison of strain-related susceptibility in two murine recovery models of global cerebral ischemia. Brain Res. 2000;868(1):1421.

    • Search Google Scholar
    • Export Citation
  • 36

    Shibata M, Ohtani R, Ihara M, Tomimoto H. White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion. Stroke. 2004;35(11):25982603.

    • Search Google Scholar
    • Export Citation
  • 37

    Hainsworth AH, Allan SM, Boltze J, Cunningham C, Farris C, Head E, et al. Translational models for vascular cognitive impairment: a review including larger species. BMC Med. 2017;15(1):16.

    • Search Google Scholar
    • Export Citation
  • 38

    Joazeiro CA, Weissman AM. RING finger proteins: mediators of ubiquitin ligase activity. Cell. 2000;102(5):549552.

  • 39

    Kamada F, Aoki Y, Narisawa A, Abe Y, Komatsuzaki S, Kikuchi A, et al. A genome-wide association study identifies RNF213 as the first moyamoya disease gene. J Hum Genet. 2011;56(1):3440.

    • Search Google Scholar
    • Export Citation
  • 40

    Kanoke A, Fujimura M, Niizuma K, Ito A, Sakata H, Sato-Maeda M, et al. Temporal profile of the vascular anatomy evaluated by 9.4-tesla magnetic resonance angiography and histological analysis in mice with the R4859K mutation of RNF213, the susceptibility gene for moyamoya disease. Brain Res. 2015;1624:497505.

    • Search Google Scholar
    • Export Citation
  • 41

    Sonobe S, Fujimura M, Niizuma K, Fujimura T, Furudate S, Nishijima Y, et al. Increased vascular MMP-9 in mice lacking RNF213: moyamoya disease susceptibility gene. Neuroreport. 2014;25(18):14421446.

    • Search Google Scholar
    • Export Citation
  • 42

    Jian Liu K, Rosenberg GA. Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med. 2005;39(1):7180.

  • 43

    Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21(12):13931400.

    • Search Google Scholar
    • Export Citation
  • 44

    Yu J, Du Q, Hu M, Zhang J, Chen J. Endothelial progenitor cells in moyamoya disease: current situation and controversial issues. Cell Transplant. 2020;29:963689720913259.

    • Search Google Scholar
    • Export Citation
  • 45

    Jung KH, Chu K, Lee ST, Park HK, Kim DH, Kim JH, et al. Circulating endothelial progenitor cells as a pathogenetic marker of moyamoya disease. J Cereb Blood Flow Metab. 2008;28(11):17951803.

    • Search Google Scholar
    • Export Citation
  • 46

    Kang HS, Moon YJ, Kim YY, Park WY, Park AK, Wang KC, et al. Smooth-muscle progenitor cells isolated from patients with moyamoya disease: novel experimental cell model. J Neurosurg. 2014;120(2):415425.

    • Search Google Scholar
    • Export Citation
  • 47

    Fujimura M, Watanabe M, Narisawa A, Shimizu H, Tominaga T. Increased expression of serum Matrix Metalloproteinase-9 in patients with moyamoya disease. Surg Neurol. 2009;72(5):476480.

    • Search Google Scholar
    • Export Citation
  • 48

    Kang HS, Kim JH, Phi JH, Kim YY, Kim JE, Wang KC, et al. Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatry. 2010;81(6):673678.

    • Search Google Scholar
    • Export Citation
  • 49

    Kobayashi H, Kabata R, Kinoshita H, Morimoto T, Ono K, Takeda M, et al. Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice. Pulm Circ. 2018;8(3):2045894018778155.

    • Search Google Scholar
    • Export Citation
  • 50

    Hiramatsu M, Hishikawa T, Tokunaga K, Kidoya H, Nishihiro S, Haruma J, et al. Combined gene therapy with vascular endothelial growth factor plus apelin in a chronic cerebral hypoperfusion model in rats. J Neurosurg. 2017;127(3):679686.

    • Search Google Scholar
    • Export Citation
  • 51

    Li Q, Gao Y, Xin W, Zhou Z, Rong H, Qin Y, et al. Meta-analysis of prognosis of different treatments for symptomatic moyamoya disease. World Neurosurg. 2019;127:354361.

    • Search Google Scholar
    • Export Citation
  • 52

    Percie du Sert N, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, et al. Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol. 2020;18(7):e3000411.

    • Search Google Scholar
    • Export Citation

Contributor Notes

Correspondence Leonel Ampie: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. leonel.ampie@nih.gov.

INCLUDE WHEN CITING DOI: 10.3171/2021.5.FOCUS21282.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • View in gallery

    Illustration of the representative technical methods for the induction of MMD in murine models. A: Technical methods for the mechanical induction of MMD with the use of an aneurysm clip to produce complete occlusion (1) and the use of incomplete ligature to induce variable degrees of stenosis of the unilateral or bilateral CCAs (2). B: The genetic methods of RNF213 gene knockdown or knockout in combination with mechanical obstruction in murine models. C: The immunological methods of MMD with an illustrative example of the ICA administration location. Made in BioRender (biorender.com).

  • 1

    Ito A, Fujimura M, Niizuma K, Kanoke A, Sakata H, Morita-Fujimura Y, et al. Enhanced post-ischemic angiogenesis in mice lacking RNF213; a susceptibility gene for moyamoya disease. Brain Res. 2015;1594:310320.

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    Sato-Maeda M, Fujimura M, Rashad S, Morita-Fujimura Y, Niizuma K, Sakata H, et al. Transient global cerebral ischemia induces RNF213, a moyamoya disease susceptibility gene, in vulnerable neurons of the rat hippocampus CA1 subregion and ischemic cortex. J Stroke Cerebrovasc Dis. 2017;26(9):19041911.

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    Sonobe S, Fujimura M, Niizuma K, Nishijima Y, Ito A, Shimizu H, et al. Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213: a susceptibility gene for moyamoya disease. Brain Res. 2014;1552:6471.

    • Search Google Scholar
    • Export Citation
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    Kobayashi H, Yamazaki S, Takashima S, Liu W, Okuda H, Yan J, et al. Ablation of Rnf213 retards progression of diabetes in the Akita mouse. Biochem Biophys Res Commun. 2013;432(3):519525.

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    Terai Y, Kamata I, Ohmoto T. Experimental study of the pathogenesis of moyamoya disease: histological changes in the arterial wall caused by immunological reactions in monkeys. Acta Med Okayama. 2003;57(5):241248.

    • Search Google Scholar
    • Export Citation
  • 21

    Yamada H, Deguchi K, Tanigawara T, Takenaka K, Nishimura Y, Shinoda J, et al. The relationship between moyamoya disease and bacterial infection. Clin Neurol Neurosurg. 1997;99(suppl 2):S221S224.

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    Hamauchi S, Shichinohe H, Houkin K. Review of past and present research on experimental models of moyamoya disease. Brain Circ. 2015;1(1):8896.

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    Wang J, Yang C, Wang H, Li D, Li T, Sun Y, et al. A new rat model of chronic cerebral hypoperfusion resulting in early-stage vascular cognitive impairment. Front Aging Neurosci. 2020;12:86.

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  • 24

    Kazumata K, Tokairin K, Sugiyama T, Ito M, Uchino H, Osanai T, et al. Association of cognitive function with cerebral blood flow in children with moyamoya disease. J Neurosurg Pediatr. 2019;25(1):17.

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  • 25

    Sasagawa A, Mikami T, Hirano T, Akiyama Y, Mikuni N. Characteristics of cerebral hemodynamics assessed by CT perfusion in moyamoya disease. J Clin Neurosci. 2018;47:183189.

    • Search Google Scholar
    • Export Citation
  • 26

    Duncombe J, Kitamura A, Hase Y, Ihara M, Kalaria RN, Horsburgh K. Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia. Clin Sci (Lond). 2017;131(19):24512468.

    • Search Google Scholar
    • Export Citation
  • 27

    Farkas E, Luiten PGM, Bari F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Brain Res Rev. 2007;54(1):162180.

    • Search Google Scholar
    • Export Citation
  • 28

    Jing Z, Shi C, Zhu L, Xiang Y, Chen P, Xiong Z, et al. Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment. J Cereb Blood Flow Metab. 2015;35(8):12491259.

    • Search Google Scholar
    • Export Citation
  • 29

    Ihara M, Taguchi A, Maki T, Washida K, Tomimoto H. A mouse model of chronic cerebral hypoperfusion characterizing features of vascular cognitive impairment. Methods Mol Biol. 2014;1135:95102.

    • Search Google Scholar
    • Export Citation
  • 30

    Washida K, Hattori Y, Ihara M. Animal models of chronic cerebral hypoperfusion: from mouse to primate. Int J Mol Sci. 2019;20(24):6176.

  • 31

    Yang Y, Kimura-Ohba S, Thompson J, Rosenberg GA. Rodent models of vascular cognitive impairment. Transl Stroke Res. 2016;7(5):407414.

    • Search Google Scholar
    • Export Citation
  • 32

    Yang G, Kitagawa K, Matsushita K, Mabuchi T, Yagita Y, Yanagihara T, Matsumoto M. C57BL/6 strain is most susceptible to cerebral ischemia following bilateral common carotid occlusion among seven mouse strains: selective neuronal death in the murine transient forebrain ischemia. Brain Res. 1997;752(1-2):209218.

    • Search Google Scholar
    • Export Citation
  • 33

    Carmichael ST. Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx. 2005;2(3):396409.

  • 34

    Canazza A, Minati L, Boffano C, Parati E, Binks S. Experimental models of brain ischemia: a review of techniques, magnetic resonance imaging, and investigational cell-based therapies. Front Neurol. 2014;5:19.

    • Search Google Scholar
    • Export Citation
  • 35

    Wellons JC III, Sheng H, Laskowitz DT, Mackensen GB, Pearlstein RD, Warner DS. A comparison of strain-related susceptibility in two murine recovery models of global cerebral ischemia. Brain Res. 2000;868(1):1421.

    • Search Google Scholar
    • Export Citation
  • 36

    Shibata M, Ohtani R, Ihara M, Tomimoto H. White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion. Stroke. 2004;35(11):25982603.

    • Search Google Scholar
    • Export Citation
  • 37

    Hainsworth AH, Allan SM, Boltze J, Cunningham C, Farris C, Head E, et al. Translational models for vascular cognitive impairment: a review including larger species. BMC Med. 2017;15(1):16.

    • Search Google Scholar
    • Export Citation
  • 38

    Joazeiro CA, Weissman AM. RING finger proteins: mediators of ubiquitin ligase activity. Cell. 2000;102(5):549552.

  • 39

    Kamada F, Aoki Y, Narisawa A, Abe Y, Komatsuzaki S, Kikuchi A, et al. A genome-wide association study identifies RNF213 as the first moyamoya disease gene. J Hum Genet. 2011;56(1):3440.

    • Search Google Scholar
    • Export Citation
  • 40

    Kanoke A, Fujimura M, Niizuma K, Ito A, Sakata H, Sato-Maeda M, et al. Temporal profile of the vascular anatomy evaluated by 9.4-tesla magnetic resonance angiography and histological analysis in mice with the R4859K mutation of RNF213, the susceptibility gene for moyamoya disease. Brain Res. 2015;1624:497505.

    • Search Google Scholar
    • Export Citation
  • 41

    Sonobe S, Fujimura M, Niizuma K, Fujimura T, Furudate S, Nishijima Y, et al. Increased vascular MMP-9 in mice lacking RNF213: moyamoya disease susceptibility gene. Neuroreport. 2014;25(18):14421446.

    • Search Google Scholar
    • Export Citation
  • 42

    Jian Liu K, Rosenberg GA. Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med. 2005;39(1):7180.

  • 43

    Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21(12):13931400.

    • Search Google Scholar
    • Export Citation
  • 44

    Yu J, Du Q, Hu M, Zhang J, Chen J. Endothelial progenitor cells in moyamoya disease: current situation and controversial issues. Cell Transplant. 2020;29:963689720913259.

    • Search Google Scholar
    • Export Citation
  • 45

    Jung KH, Chu K, Lee ST, Park HK, Kim DH, Kim JH, et al. Circulating endothelial progenitor cells as a pathogenetic marker of moyamoya disease. J Cereb Blood Flow Metab. 2008;28(11):17951803.

    • Search Google Scholar
    • Export Citation
  • 46

    Kang HS, Moon YJ, Kim YY, Park WY, Park AK, Wang KC, et al. Smooth-muscle progenitor cells isolated from patients with moyamoya disease: novel experimental cell model. J Neurosurg. 2014;120(2):415425.

    • Search Google Scholar
    • Export Citation
  • 47

    Fujimura M, Watanabe M, Narisawa A, Shimizu H, Tominaga T. Increased expression of serum Matrix Metalloproteinase-9 in patients with moyamoya disease. Surg Neurol. 2009;72(5):476480.

    • Search Google Scholar
    • Export Citation
  • 48

    Kang HS, Kim JH, Phi JH, Kim YY, Kim JE, Wang KC, et al. Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatry. 2010;81(6):673678.

    • Search Google Scholar
    • Export Citation
  • 49

    Kobayashi H, Kabata R, Kinoshita H, Morimoto T, Ono K, Takeda M, et al. Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice. Pulm Circ. 2018;8(3):2045894018778155.

    • Search Google Scholar
    • Export Citation
  • 50

    Hiramatsu M, Hishikawa T, Tokunaga K, Kidoya H, Nishihiro S, Haruma J, et al. Combined gene therapy with vascular endothelial growth factor plus apelin in a chronic cerebral hypoperfusion model in rats. J Neurosurg. 2017;127(3):679686.

    • Search Google Scholar
    • Export Citation
  • 51

    Li Q, Gao Y, Xin W, Zhou Z, Rong H, Qin Y, et al. Meta-analysis of prognosis of different treatments for symptomatic moyamoya disease. World Neurosurg. 2019;127:354361.

    • Search Google Scholar
    • Export Citation
  • 52

    Percie du Sert N, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, et al. Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol. 2020;18(7):e3000411.

    • Search Google Scholar
    • Export Citation

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