Insights into potential targeted nonsurgical therapies for the treatment of moyamoya disease

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  • 1 Division of Neurosurgery, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota;
  • | 2 Department of Neurosurgery, Louisiana State University Health Shreveport School of Medicine, Shreveport, Louisiana;
  • | 3 Department of Brain & Spine Surgery, Naval Medical Center Portsmouth, Portsmouth, Virginia;
  • | 4 Division of Neurosurgery, Department of Surgery, Uniformed Services University, Bethesda, Maryland; and
  • | 5 Department of Neurosurgery, University of Cincinnati School of Medicine, Cincinnati, Ohio
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Since its initial description in 1957 as an idiopathic disease, moyamoya disease has proved challenging to treat. Although the basic pathophysiology of this disease involves narrowing of the terminal carotid artery with compensatory angiogenesis, the molecular and cellular mechanisms underlying these changes are far more complex. In this article, the authors review the literature on the molecular and cellular pathophysiology of moyamoya disease with an emphasis on potential therapeutic targets.

ABBREVIATIONS

ABMSC = autologous bone marrow stem cell; bFGF = basic fibroblast growth factor; EPC = endothelial progenitor cell; ICA = internal carotid artery; MMD = moyamoya disease; MMP = matrix metalloproteinase; RNF213 = ring finger protein 213; SMC = smooth muscle cell; VEGF = vascular endothelial growth factor; VSMC = vascular SMC.

Since its initial description in 1957 as an idiopathic disease, moyamoya disease has proved challenging to treat. Although the basic pathophysiology of this disease involves narrowing of the terminal carotid artery with compensatory angiogenesis, the molecular and cellular mechanisms underlying these changes are far more complex. In this article, the authors review the literature on the molecular and cellular pathophysiology of moyamoya disease with an emphasis on potential therapeutic targets.

ABBREVIATIONS

ABMSC = autologous bone marrow stem cell; bFGF = basic fibroblast growth factor; EPC = endothelial progenitor cell; ICA = internal carotid artery; MMD = moyamoya disease; MMP = matrix metalloproteinase; RNF213 = ring finger protein 213; SMC = smooth muscle cell; VEGF = vascular endothelial growth factor; VSMC = vascular SMC.

First described in 1957, moyamoya disease (MMD) is characterized by idiopathic progressive narrowing of the bilateral intracranial internal carotid arteries (ICAs) with compensatory hyperplasia of the lenticulostriate arteries and growth of numerous small vessels to maintain cerebral perfusion.1 This can be differentiated from moyamoya syndrome, in which the vessel narrowing is secondary to an underlying disease such as atherosclerosis, neurofibromatosis type 1, or tuberous sclerosis, although some researchers believe that the pathophysiology is similar and that these diseases represent susceptibility conditions. At present, treatment options for MMD are limited to treating the sequelae of the disease, as there are currently no therapies that have been shown to halt, slow, or even reverse the underlying pathophysiological changes. Recent studies detailing anatomical, inflammatory, proteomic, cellular, and genetic contributors to the pathophysiology of MMD have carved a pathway that may lead to nonsurgical therapeutic options (Fig. 1). These contributors, though viewed as separate entities molecularly, are intertwined considerably and interact with each other in complex ways that are still being unraveled. In this paper, we review research on the molecular drivers of MMD with an emphasis on targets for future disease-modifying medical treatments.2–5

FIG. 1.
FIG. 1.

Contributors to MMD pathology. TGF-β = transforming growth factor beta. Copyright Sandeep Kandregula. Published with permission.

Anatomical Abnormalities in MMD

ICA Narrowing

A key physiological derangement in MMD is the progressive narrowing of the terminal ICAs. This narrowing, combined with the compensatory development of fragile collateral vessels, was first described by Suzuki and Takaku.1 Collaterals may form through enlargement of the lenticulostriate and thalamoperforating arteries, anterior choroidal and posterior ethmoidal arteries, and dural arteries.6 Histopathological studies have demonstrated progressive intimal fibrocellular thickening with a paucity of lipid.7 A study by Takagi et al. found that the ICAs in patients with MMD have a thinner media and a very thick intima compared with controls.8 There are also fewer normal smooth muscle cells (SMCs), a fragmented elastic lamina, and fibrin deposits in the vessel walls, along with microaneurysms.9 Masuda et al. examined the vessels of 6 patients with MMD and discovered that the thickened intima was mainly composed of synthetic SMCs, an immature phenotype seen predominantly in embryonic development that is associated with a high degree of proliferation, migration, and extracellular matrix production (Fig. 2). Increased numbers of T cells and macrophages are also seen in the vessel walls, suggesting an inflammatory component to MMD.11

FIG. 2.
FIG. 2.

Changes in the cerebral arterial wall in MMD. Copyright Sandeep Kandregula. Published with permission.

Angiogenesis, Vasculogenesis, and Arteriogenesis

Spontaneous vessel growth is a central process in MMD. This may be classified as angiogenesis, vasculogenesis, or arteriogenesis. Angiogenesis refers to new vessel formation by sprouting, branching, and lumen creation. This typically occurs as the result of a pathological process such as hypoxia or ischemia and requires circulating endothelial cells to be remodeled into a new vessel network.3,10,12 Vasculogenesis refers to formation of new blood vessels in utero and in the immediate postnatal period.3 This process requires endothelial progenitor cells (EPCs) that migrate from the bone marrow in response to local stimuli. Arteriogenesis is collateralization through remodeling of existing artery-artery and arteriole-arteriole anastomoses.13 Pressure differences between perfusion territories create an increase in fluid shear forces.3 These forces activate chemoattractive molecules such as monocyte chemoattractive protein 1 and cellular adhesion molecules. Monocyte recruitment brings along cytokines and growth factors needed for vessel formation. Among these, basic fibroblast growth factor (bFGF) and matrix metalloproteinases (MMPs) are the most widely studied in the context of MMD. Interestingly, patients with MMD, compared with those with other forms of chronic cerebral ischemia, have an increased capacity for vessel collateralization.14 It is believed that all three of these processes—angiogenesis, vasculogenesis, and arteriogenesis—are involved in the development of moyamoya vessels, although the involvement of vasculogenesis is controversial in this context.

Inflammation in MMD Pathophysiology and Animal Model Development

Inflammation is thought to have a significant role in the pathogenesis of MMD. Kasai et al. developed the first animal model of MMD in 1982 by injecting horse or cat serum intravenously or intramuscularly into mongrel dogs to induce a serum sickness–like inflammatory reaction.15 This was motivated by the observation that many patients with MMD had a history of inflammation above the neck, mainly chronic tonsillitis. When the dogs were euthanized, changes that are consistent with MMD such as intimal thickening, tortuosity of elastic lamina, and muscle layer necrosis localized to the terminal portion of the ICA were detected. Smooth muscle was also found to play a pivotal role in this model, as lesioning of the superior cervical ganglion mitigated the MMD-like changes, and stimulation augmented it.15

Ezura et al. used a similar serum sickness model by injecting horse serum into rabbits.16 They found a vasculitis in the systemic circulation, but they did not see typical MMD changes within the cerebral vasculature. However, after injecting anti-horse serum antibodies into the CSF via the cisterna magna, leukocyte infiltration was seen in the cerebral arterial walls. The authors concluded that circulating immune complexes were not enough to induce arterial lesions; rather, an interaction must occur at the arterial wall for lesions to develop.

Yamada et al. found that patients with MMD had significantly higher serum levels of Propionibacterium acnes antibody, immunoglobulin M, transferrin, and α-2-macroglobulin, suggesting a postinfectious inflammatory etiology.17 They injected P. acnes into the carotid bifurcation of rats and found coarse, disrupted, and duplicated internal elastic membranes in the intracranial ICA. However, intimal changes and stenotic lesions were not induced.

Expanding on the hypothesis of an immunological pathogenesis, Kamata et al. injected muramyl dipeptide, the smallest structural unit of the bacterial cell wall that modulates an immune response, into the ICA bifurcation of cats.18 This was combined with a lactic acid and glycolic acid 50:50 copolymer to serve as an embolic source of ICA occlusion. The combination was injected unilaterally. Although the embolism did create an occlusion in the unilateral ICA, the distal ICA was preserved on angiography via a well-developed vascular route between the external carotid artery and ICA. Histological findings of the ICA included mild intimal thickening accompanying focal folding, and duplication of the internal elastic lamina most prominently in the terminal portion of the ICA. In contrast, muramyl dipeptide injected into monkeys, which have a cerebrovascular architecture more similar to humans, did not result in pathophysiological changes similar to MMD.19

Finally, a prospective randomized controlled trial performed in humans gauged the efficacy of postoperative autologous bone marrow stem cell (ABMSC) mobilization and antiinflammatory medication versus surgery alone.20 The ABMSCs were mobilized via recombinant human granulocyte colony stimulating factor and recombinant human granulocyte-macrophage colony stimulating factor in addition to utilizing the antiinflammatory properties of dexamethasone. The treatment group showed statistically significant increases in measures for activities of daily living compared with the control group at 3 and 6 months postoperatively; NIH stroke scale scores were significantly lower in the treatment group at 3 and 6 months postoperatively, and Chinese stroke scale scores were significantly lower in the treatment group at 1 and 3 months postoperatively. This study showed that antiinflammatory agents may be useful for improving postoperative outcomes in patients with MMD, but more specific studies are needed, particularly those addressing primary medical management with these agents. Nonetheless, inflammatory cascade modulators may be a promising class of therapeutic agents in MMD.

Cellular Contributors to MMD

EPCs are bone marrow-derived cells, typically displaying CD34, CD133, and VEGFR positivity, that are recruited by the systemic circulation via secretion of proangiogenic cytokines in response to hypoxia or vascular injury.3 In regions of adult vasculogenesis, EPCs upregulate different growth factors such as vascular endothelial growth factor (VEGF), granulocyte colony stimulating factor, and stromal cell-derived factor–1α.21

Patients with MMD have been found to have increased circulating levels of these EPCs in some studies,22,23 although Jung et al. described a decreased number of EPC colony-forming units and impaired function in children.24–26 Tinelli et al. found a decreased number of EPCs in adult patients with MMD with preserved normal function.27 The contrasting nature of these results is epitomic of the research still needed to discover the true role of EPCs in the pathogenesis of MMD. The abnormal proliferation of these cells is thought to be responsible for the eccentric fibrocellular thickening of the intima, which is one of the most important MMD histopathological features.8 This hypothesis has been corroborated by ex vivo and in vitro studies. Sugiyama et al. found that staining for these cells in supraclinoid ICAs from patients with MMD revealed clusters of EPCs within the occlusive lesion, particularly in the superficial layer of the intima near the lumen of the vessels.28 Kang et al. found that circulating smooth muscle progenitor cells found in patients with MMD could be differentiated from circulating EPCs, suggesting that these EPCs contribute to the SMC proliferation in stenotic lesions in MMD.29 In a study performed by Nagata et al., EPCs and peripheral blood mononuclear cells (PBMNCs) were cultured from the blood of patients with MMD.30 They found that the PBMNCs insufficiently produced interleukin-10 and the EPCs cultured from patients with MMD, that would normally differentiate and divide in the presence of interleukin-10, were less responsive when compared with control EPCs. This suggests that an impaired EPC differentiation may lead to the abnormal vascular phenotype seen in MMD.

EPCs have emerged as a probable critical player in the pathogenesis of MMD. Modulation of the replication and functionality of these cells may be an important therapeutic target in slowing ICA terminus narrowing.

Proteomic Contributors to MMD

Basic Fibroblast Growth Factor

In patients with MMD, bFGF has been found at elevated levels in the CSF and within endothelial cells, fibroblasts, and SMCs.31–33 Gene expression is also increased.34 The role of bFGF as a mitogen for vascular endothelial cells and SMCs has been documented,35 prompting division, migration, and invasion in these types of cells.36,37 These observations suggest that bFGF is a key mediator in the intimal thickening seen in MMD.

In addition to intimal thickening, however, bFGF may contribute to the compensatory angiogenesis and collateralization seen in this disease.38 Because of this, targeting bFGF as a potential therapy for MMD may prove challenging. Systemic medications that block this molecule could result in ischemic events as collateralization could not occur in other normal tissues. Recombinant bFGF given to a rabbit model of acute lower-limb ischemia resulted in enhanced angiogenesis and arteriogenesis.39 Basic FGF may also have a neuroprotective effect in traumatic brain injury.40

Matrix Metalloproteinases

MMPs are a family of zinc-dependent endopeptidases that are involved in degradation of extracellular molecules.41,42 They play a role in tissue remodeling during angiogenesis and can influence endothelial cell function as well as vascular SMC (VSMC) migration, proliferation, Ca2+ signaling, and contraction. Vascular smooth muscle growth may be induced via the ability of MMPs to cleave growth factor binding proteins and matrix molecules,43 as well as facilitate VSMC proliferation by promoting permissive interactions between VSMCs and components of the extracellular matrix, possibly via integrin-mediated pathways.44

Studies of ring finger protein 213 (RNF213) knockout mice, an animal model of MMD, have shown an increase in tissue MMP-9 under ischemic conditions.45 As Kaku et al. have shown that early narrowing of the outer diameter of the ICA is intrinsic in moyamoya,46 these findings may represent early constrictive remodeling in the ICA of RNF213 knockout mice. In a histological analysis, increased MMP-9 levels in the vessels of patients with MMD were associated with an increased extracellular gelatinolytic activity and a significantly decreased level of type 4 collagen.47

Several MMP inhibitors have been studied, but doxycycline remains the only FDA-approved MMP inhibitor; however, it has not yet been studied as a potential therapeutic agent for MMD.48 Jacobsen et al. described the development and design of MMP inhibitors, their selectivity, and potential systemic effects and benefits with a potential postischemic neuroprotective effect in mice models.49 Although more research is needed, MMP inhibition could prove promising as a therapeutic option for MMD.

Vascular Endothelial Growth Factor

VEGF is a family of growth factors with important proangiogenic activity, having mitogenic and antiapoptotic effects on endothelial cells, increasing vascular permeability, and promoting cell migration.50 In ischemic disease, VEGF is intricately involved in cerebral angiogenesis51 and is a prime regulator of endothelial cell proliferation.52 Park et al. reasoned that certain polymorphisms in the VEGF gene may cause cerebral ischemia in patients with MMD.51 Other polymorphisms have been associated with synangiosis-induced favorable postoperative collateralization.53 VEGF overexpression has been shown in histological studies of MMD54 and has been suggested to contribute to the formation of fragile collateral vessels and be responsible for occasional microbleeds.55 VEGF overexpression is also known to pathologically increase the permeability of the blood-brain barrier, leading to edema.56

Therapeutic neovascularization induced by recombinant VEGF may be a potential therapy for MMD; however, it has not been particularly promising in human studies to date. A randomized controlled trial for myocardial ischemia has demonstrated no significant increase in myocardial perfusion and function in patients given recombinant VEGF versus a placebo.57 This may be because endogenous VEGF is formed at adequate levels during periods of tissue ischemia. In animal studies, the administration of VEGF has been shown to enhance angiogenesis in the ischemic penumbra and decrease stroke burden.58,65 In contrast, VEGF blockade has also been shown to be therapeutic following ischemic events in animal studies as it decreases breakdown of the blood-brain barrier and subsequent cytotoxic edema, hemorrhagic transformation, and pressure-related further ischemia.56 Finally, an in vitro study using recombinant human VEGF on hippocampal neurons undergoing hypoxia relayed a neuroprotective effect, reducing cell death in these cultures.59

Although some of these studies seem to contradict each other, it is certain that VEGF plays a vital role in recovery from ischemic events. Using recombinant VEGF, or a blockade in a moyamoya model, could provide vital information of the possible therapeutic effects.

Genetic Contributors to MMD

RNF213, also known as mysterin, is a 548-kD protein typically coded for at the 17q25 locus.60 Though its pathological role in MMD is unknown, it is widely accepted as a major susceptibility factor in MMD.25,61 Multiple variants of the RNF213 gene, most of which are single-nucleotide polymorphisms, have been implicated in MMD,62 with some evidence to suggest that different variants may have different clinical and radiographic manifestations.63 Recent studies have highlighted its function in lipid metabolism modulating lipotoxicity,64 fat storage, and lipid droplet formation.65 Ahel et al. described this protein as a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism.60 RNF213 has also been shown to be involved in coordinating the nonmitochondrial oxygenation response to cellular hypoxia.66 It is also capable of affecting the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and can directly activate NF-κB, influencing inflammatory cytokines and, thus, angiogenesis.

Recent in vivo studies in mice have shown that RNF213 knockout is not sufficient to develop disease; however, thinning of the media layers of the ICA may be induced following ligation of the common carotid artery.45,67 Zebrafish RNF213 knockout models have demonstrated severely abnormal sprouting vessels in the head region, particularly the optic vessels.26 Further studies by Ito et al. generated an ischemic insult to RNF213-deficient mice and found that postischemic angiogenesis was significantly enhanced in these mice, suggesting the potential role of RNF213 in the development of abnormal vasculature in chronic ischemic states.68 Conversely, RNF213 knock-in mice did not develop MMD under normal circumstances.69 Fujimura et al. have speculated that the lack of disease development without ischemic insult could be the product of low penetrance of RNF213 polymorphisms and may highlight the importance of environmental or other genetic factors in the disease.4,62

With knowledge of the mechanisms and structure of RNF213 protein growth, targeted therapy could develop in the future. The recently elucidated structure of the RNF213 protein60 may pave the way for recombinant forms to be developed as a therapy. Because studies have shown that RNF213 knockout, coupled with ischemia, can cause moyamoya-type changes,26,45,70 the addition of this molecule may prove beneficial in the prevention of the disease in those screened as having RNF213 mutations.

Conclusions

Like most diseases, MMD is a complex condition that likely results from an interplay of different genetic, molecular, and environmental influences. Nonetheless, several important molecular and cellular cascades including inflammation, EPCs, bFGF, MMPs, VEGF, and RNF213 are all promising potential targets for medical therapies that may slow or stop the progression of the disease (Fig. 3). In establishing reliable animal models for MMD, medical therapeutics can be trialed in hopes of bringing them to human use. With continued research into diseases like MMD, we come closer to Cushing’s dream—a day when a surgeon will be appointed who has no hands, “for the operative part is the least part of the work.”

FIG. 3.
FIG. 3.

Molecular and cellular pathways involved in MMD. IL-1β = interleukin 1-beta; SPC = smooth muscle progenitor cell. Copyright Sandeep Kandregula. Published with permission.

Disclaimer

The views expressed in this article reflect the results of research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the United States Government. Neither the Department of the Navy nor any other component of the Department of Defense has approved, endorsed, or authorized this article.

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: Kosty, Goehner, Carroll, Zuccarello, Guthikonda. Drafting the article: Kosty, Goehner, Kandregula. Critically revising the article: Kosty, Goehner. Reviewed submitted version of manuscript: Kosty.

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    Blecharz-Lang KG, Prinz V, Burek M, Frey D, Schenkel T, Krug SM, et al. Gelatinolytic activity of autocrine matrix metalloproteinase-9 leads to endothelial de-arrangement in Moyamoya disease. J Cereb Blood Flow Metab. 2018;38(11):19401953.

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    Chen Q, Jin M, Yang F, Zhu J, Xiao Q, Zhang L. Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators Inflamm. 2013;2013:928315.

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    Jacobsen JA, Major Jourden JL, Miller MT, Cohen SM. To bind zinc or not to bind zinc: an examination of innovative approaches to improved metalloproteinase inhibition. Biochim Biophys Acta. 2010;1803(1):7294.

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  • 50

    Melincovici CS, Boşca AB, Şuşman S, Mărginean M, Mihu C, Istrate M, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol. 2018;59(2):455467.

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  • 51

    Park YS, Jeon YJ, Kim HS, Chae KY, Oh SH, Han IB, et al. The role of VEGF and KDR polymorphisms in moyamoya disease and collateral revascularization. PLoS One. 2012;7(10):e47158.

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  • 52

    La Rosa S, Uccella S, Finzi G, Albarello L, Sessa F, Capella C. Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. Hum Pathol. 2003;34(1):1827.

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  • 53

    Park YS, Jeon YJ, Lee BE, Kim TG, Choi JU, Kim DS, Kim NK. Association of the miR-146aC>G, miR-196a2C>T, and miR-499A>G polymorphisms with moyamoya disease in the Korean population. Neurosci Lett. 2012;521(1):7175.

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    • Export Citation
  • 54

    Takekawa Y, Umezawa T, Ueno Y, Sawada T, Kobayashi M. Pathological and immunohistochemical findings of an autopsy case of adult moyamoya disease. Neuropathology. 2004;24(3):236242.

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    • Export Citation
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    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
  • 56

    van Bruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, et al. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest. 1999;104(11):16131620.

    • Search Google Scholar
    • Export Citation
  • 57

    Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, et al. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation. 2003;107(10):13591365.

    • Search Google Scholar
    • Export Citation
  • 58

    Pignataro G, Ziaco B, Tortiglione A, Gala R, Cuomo O, Vinciguerra A, et al. Neuroprotective effect of VEGF-mimetic peptide QK in experimental brain ischemia induced in rat by middle cerebral artery occlusion. ACS Chem Neurosci. 2015;6(9):15171525.

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    • Export Citation
  • 59

    Svensson B, Peters M, König HG, Poppe M, Levkau B, Rothermundt M, et al. Vascular endothelial growth factor protects cultured rat hippocampal neurons against hypoxic injury via an antiexcitotoxic, caspase-independent mechanism. J Cereb Blood Flow Metab. 2002;22(10):11701175.

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    • Export Citation
  • 60

    Ahel J, Lehner A, Vogel A, Schleiffer A, Meinhart A, Haselbach D, Clausen T. Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism. Elife. 2020;9:e56185.

    • Search Google Scholar
    • Export Citation
  • 61

    Hu J, Luo J, Chen Q. The susceptibility pathogenesis of moyamoya disease. World Neurosurg. 2017;101:731741.

  • 62

    Bang OY, Fujimura M, Kim SK. The pathophysiology of moyamoya disease: an update. J Stroke. 2016;18(1):1220.

  • 63

    Kleinloog R, Regli L, Rinkel GJ, Klijn CJ. Regional differences in incidence and patient characteristics of moyamoya disease: a systematic review. J Neurol Neurosurg Psychiatry. 2012;83(5):531536.

    • Search Google Scholar
    • Export Citation
  • 64

    Piccolis M, Bond LM, Kampmann M, Pulimeno P, Chitraju C, Jayson CBK, et al. Probing the global cellular responses to lipotoxicity caused by saturated fatty acids. Mol Cell. 2019;74(1):3244.e8.

    • Search Google Scholar
    • Export Citation
  • 65

    Sugihara M, Morito D, Ainuki S, Hirano Y, Ogino K, Kitamura A, et al. The AAA+ ATPase/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets. J Cell Biol. 2019;218(3):949960.

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    • Export Citation
  • 66

    Banh RS, Iorio C, Marcotte R, Xu Y, Cojocari D, Rahman AA, et al. PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. Nat Cell Biol. 2016;18(7):803813.

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    • Export Citation
  • 67

    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
  • 68

    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.

    • Search Google Scholar
    • Export Citation
  • 69

    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
  • 70

    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.

    • Search Google Scholar
    • Export Citation

Contributor Notes

Correspondence Jennifer A. Kosty: Louisiana State University Health Shreveport School of Medicine, Shreveport, LA. jkosty@lsuhsc.edu.

INCLUDE WHEN CITING DOI: 10.3171/2021.6.FOCUS21289.

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

    Contributors to MMD pathology. TGF-β = transforming growth factor beta. Copyright Sandeep Kandregula. Published with permission.

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    Changes in the cerebral arterial wall in MMD. Copyright Sandeep Kandregula. Published with permission.

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    Molecular and cellular pathways involved in MMD. IL-1β = interleukin 1-beta; SPC = smooth muscle progenitor cell. Copyright Sandeep Kandregula. Published with permission.

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    Blecharz-Lang KG, Prinz V, Burek M, Frey D, Schenkel T, Krug SM, et al. Gelatinolytic activity of autocrine matrix metalloproteinase-9 leads to endothelial de-arrangement in Moyamoya disease. J Cereb Blood Flow Metab. 2018;38(11):19401953.

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    • Export Citation
  • 48

    Chen Q, Jin M, Yang F, Zhu J, Xiao Q, Zhang L. Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators Inflamm. 2013;2013:928315.

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    • Export Citation
  • 49

    Jacobsen JA, Major Jourden JL, Miller MT, Cohen SM. To bind zinc or not to bind zinc: an examination of innovative approaches to improved metalloproteinase inhibition. Biochim Biophys Acta. 2010;1803(1):7294.

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    • Export Citation
  • 50

    Melincovici CS, Boşca AB, Şuşman S, Mărginean M, Mihu C, Istrate M, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol. 2018;59(2):455467.

    • Search Google Scholar
    • Export Citation
  • 51

    Park YS, Jeon YJ, Kim HS, Chae KY, Oh SH, Han IB, et al. The role of VEGF and KDR polymorphisms in moyamoya disease and collateral revascularization. PLoS One. 2012;7(10):e47158.

    • Search Google Scholar
    • Export Citation
  • 52

    La Rosa S, Uccella S, Finzi G, Albarello L, Sessa F, Capella C. Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. Hum Pathol. 2003;34(1):1827.

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    • Export Citation
  • 53

    Park YS, Jeon YJ, Lee BE, Kim TG, Choi JU, Kim DS, Kim NK. Association of the miR-146aC>G, miR-196a2C>T, and miR-499A>G polymorphisms with moyamoya disease in the Korean population. Neurosci Lett. 2012;521(1):7175.

    • Search Google Scholar
    • Export Citation
  • 54

    Takekawa Y, Umezawa T, Ueno Y, Sawada T, Kobayashi M. Pathological and immunohistochemical findings of an autopsy case of adult moyamoya disease. Neuropathology. 2004;24(3):236242.

    • Search Google Scholar
    • Export Citation
  • 55

    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
  • 56

    van Bruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, et al. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest. 1999;104(11):16131620.

    • Search Google Scholar
    • Export Citation
  • 57

    Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, et al. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation. 2003;107(10):13591365.

    • Search Google Scholar
    • Export Citation
  • 58

    Pignataro G, Ziaco B, Tortiglione A, Gala R, Cuomo O, Vinciguerra A, et al. Neuroprotective effect of VEGF-mimetic peptide QK in experimental brain ischemia induced in rat by middle cerebral artery occlusion. ACS Chem Neurosci. 2015;6(9):15171525.

    • Search Google Scholar
    • Export Citation
  • 59

    Svensson B, Peters M, König HG, Poppe M, Levkau B, Rothermundt M, et al. Vascular endothelial growth factor protects cultured rat hippocampal neurons against hypoxic injury via an antiexcitotoxic, caspase-independent mechanism. J Cereb Blood Flow Metab. 2002;22(10):11701175.

    • Search Google Scholar
    • Export Citation
  • 60

    Ahel J, Lehner A, Vogel A, Schleiffer A, Meinhart A, Haselbach D, Clausen T. Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism. Elife. 2020;9:e56185.

    • Search Google Scholar
    • Export Citation
  • 61

    Hu J, Luo J, Chen Q. The susceptibility pathogenesis of moyamoya disease. World Neurosurg. 2017;101:731741.

  • 62

    Bang OY, Fujimura M, Kim SK. The pathophysiology of moyamoya disease: an update. J Stroke. 2016;18(1):1220.

  • 63

    Kleinloog R, Regli L, Rinkel GJ, Klijn CJ. Regional differences in incidence and patient characteristics of moyamoya disease: a systematic review. J Neurol Neurosurg Psychiatry. 2012;83(5):531536.

    • Search Google Scholar
    • Export Citation
  • 64

    Piccolis M, Bond LM, Kampmann M, Pulimeno P, Chitraju C, Jayson CBK, et al. Probing the global cellular responses to lipotoxicity caused by saturated fatty acids. Mol Cell. 2019;74(1):3244.e8.

    • Search Google Scholar
    • Export Citation
  • 65

    Sugihara M, Morito D, Ainuki S, Hirano Y, Ogino K, Kitamura A, et al. The AAA+ ATPase/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets. J Cell Biol. 2019;218(3):949960.

    • Search Google Scholar
    • Export Citation
  • 66

    Banh RS, Iorio C, Marcotte R, Xu Y, Cojocari D, Rahman AA, et al. PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. Nat Cell Biol. 2016;18(7):803813.

    • Search Google Scholar
    • Export Citation
  • 67

    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
  • 68

    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.

    • Search Google Scholar
    • Export Citation
  • 69

    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
  • 70

    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.

    • Search Google Scholar
    • Export Citation

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