Advances in moyamoya disease: pathogenesis, diagnosis, and therapeutic interventions

Abstract

Moyamoya disease (MMD) is a type of cerebrovascular disease characterized by occlusion of the distal end of the internal carotid artery and the formation of collateral blood vessels. Over the past 20 years, the landscape of research on MMD has significantly transformed. In this review, we provide insights into the pathogenesis, diagnosis, and therapeutic interventions in MMD. The development of high-throughput sequencing technology has expanded our understanding of genetic susceptibility, identifying MMD-related genes beyond RNF213, such as ACTA2, DIAPH1, HLA, and others. The genetic susceptibility of MMD to its pathological mechanism was summarized and discussed. Based on the second-hit theory, the influences of inflammation, immunity, and environmental factors on MMD were also appropriately summarized. Despite these advancements, revascularization surgery remains the primary treatment for MMD largely because of the lack of effective in vivo and in vitro models. In this study, 16 imaging diagnostic methods for MMD were summarized. Regarding therapeutic intervention, the influences of drugs, endovascular procedures, and revascularization surgeries on patients with MMD were discussed. Future research on the central MMD vascular abnormalities and peripheral circulating factors will provide a more comprehensive understanding of the pathogenic mechanisms of MMD.

Keywords: genetic susceptibility; immunity; moyamoya disease; pathogenesis; pathological angiogenesis.

FIGURE 1

Superficial temporal artery intimal thickening causing hemadostenosis. (A) In moyamoya disease, the vessel lumen is markedly narrowed. Scale bar: 300 µm. (B) The wall of the stenotic vessel is notably thickened. Scale bar: 100 µm. (C) The intima is hyperplastic, and the cells are arranged in a disordered fashion. The structure of the internal elastic membrane is changed. Scale bar: 50 µm.

FIGURE 2

Overview of DNA methylation involved in moyamoya disease. In the nucleus, under the action of DNA methyltransferases, a methyl group is covalently bound to the 5′ carbon of the cytosine in CpG dinucleotides. The level of DNA methylation gives rise to changes in the expression levels of certain genes in moyamoya disease. This has an impact on certain processes related to vascular, such as endothelial tube formation, endothelial cell proliferation, vascular injury response, and so on. BRCA1, breast cancer type 1 susceptibility protein; GACNT2, GalNAc‐type O‐glycosylation and its initiating GalNAc transferase 2; HSPG2, heparan sulfate proteoglycan 2; JAK3, Janus kinase 3; KCNMA1, potassium large conductance calcium‐activated channel subfamily M alpha member 1; RBM33, RNA‐binding protein 33; SORT1, Sortilin 1; SOX6, SRY‐box transcription factor 6.

FIGURE 3

Mechanism of immune infiltration in moyamoya disease (MMD). In moyamoya disease, immune cells and cytokines exert an effect on the vascular endothelial cells and smooth muscle cells. Treg cells secrete TGF‐β and IL‐10. Th17 cells secrete IL‐17 and TNF‐α.M2 microglia secrete ROS. CD163 promotes the regulation of macrophagocyte for VSMC proliferation. Various cytokines directly or indirectly modulate the proliferation and migration of vascular endothelial cells and smooth muscle cells, which may be connect with intimal thickening and vascular compensatory hyperplasia in MMD. IL, interleukin; ROS, reactive oxygen species; TGF‐β, transforming growth factor‐beta; TNF‐α, tumor necrosis factor‐alpha; Treg cell, regulatory T cell; VSMC, vascular smooth muscle cell.

FIGURE 4

Multiomics in the moyamoya disease. The figure illustrates the multiomics approach to moyamoya disease. DIA mass spectrometry: Proteins are extracted from serum samples. After undergoing treatment with trypsin, proteins are transformed into peptide segments. Following binding and fractionation, mass spectrometry analysis is carried out. Whole‐exome sequencing: Double‐stranded DNA is extracted from whole blood samples. DNA is cut by the ligation‐based method to obtain exons. The capture array hybridization is employed for target enrichment analysis; Untargeted metabolomics analysis: Metabolites are extracted from serum samples. The samples are introduced into the chromatography system and undergo mass spectrometry analysis. DIA, data‐independent acquisition mass spectrometry.