Experimental animal models for moyamoya disease and treatment: a pathogenesis-oriented scoping review

Abstract

OBJECTIVE Moyamoya disease (MMD) is an intracranial steno-occlusive pathology characterized by progressive narrowing of proximal large vessels, including the terminal internal carotid arteries (ICAs), middle cerebral arteries, or anterior cerebral arteries. Named for the “puff of smoke” appearance of the anomalous vascularization visualized on cerebral angiography, MMD lacks a well-defined etiology, although significant insights have been made, including the identification of a susceptibility gene, RNF213, in humans with the disease. A limitation to advancing the understanding and treatment of MMD has been the lack of experimental animal models that authentically reflect the clinical pathogenesis. In an effort to analyze characteristics of currently available models and identify strategies for future model generation, the authors performed a scoping review of experimental animal models that have been used to study MMD. METHODS A systematic search of PubMed, Web of Science, and Scopus was performed to identify articles describing animal models used to study MMD. Additional articles were identified via citation searching. Study selection and data extraction were performed by two independent reviewers based on defined inclusion and exclusion criteria. RESULTS A total of 44 articles were included for full-text review. The methods used to generate these animal models were broadly classified as surgical (n = 25, 56.8%), immunological (n = 7, 15.9%), genetic (n = 6, 13.6%), or a combination (n = 6, 13.6%). Surgical models typically involved permanent ligation of one or both of the common carotid arteries or ICAs to produce chronic cerebral hypoperfusion. Genetic models utilized known MMD or cerebrovascular disease-related genes, such as RNF213 or ACTA2, to induce heritable cerebral vasculopathy. Finally, immunological models attempted to induce vasculitis-type pathology by recapitulating the inflammatory milieu thought to underlie MMD. CONCLUSIONS Models generated for MMD have involved three general approaches: surgical, immunological, and genetic. Although each reflects a key aspect of MMD pathogenesis, the failure of any individual model to recapitulate the development, progression, and consequences of the disease underscores the importance of future work in developing a multietiology model.

Identification of oxidative phosphorylation-related genes in moyamoya disease by combining bulk RNA-sequencing analysis and machine learning

“…However, owing to the unclear mechanism of MMD, there is a lack of effective drugs to prevent its progression, as well as effective Frontiers in Genetics frontiersin.org animal models (Rallo et al, 2021;Ihara et al, 2022). Although some biological targets have recently been identified by genomics, proteomics, or other methods, animal modeling and drug research based on these targets have achieved unsatisfactory results (Rallo et al, 2021;Ihara et al, 2022). This suggests that other mechanisms may be involved in MMD development.…”

Metabolomic signatures associated with pathological angiogenesis in moyamoya disease

“…We constructed a cell model of moyamoya disease using serum stimulation to verify the function of the above metabolites. 6 The apoptotic ratios of HBVSMCs in the ischaemic and haemorrhagic subgroups were significantly lower than HC (Figure 2A,B). Cell viability was significantly increased in three MMD groups.…”

Upregulated Cytoskeletal Proteins Promote Pathological Angiogenesis in Moyamoya Disease

“…7 So far, due to its unknown pathogenesis, no model accurately summarizes the pathological changes in vascular intimal hyperplasia in MMD. 8,9 Recent studies of the DIAPH1 gene mutation in patients of European ancestry have raised the possibility that actin remodeling may be involved in the pathogenesis of MMD, but no specific studies have been performed to test this hypothesis. 10 Proteomic analysis of exosomes from hemorrhagic MMD has suggested that altered expression levels of the actin proteins cofilin and ARP2/3 are involved in the cell cycle of these patients compared with healthy controls.…”

“…7 So far, due to its unknown pathogenesis, no model accurately summarizes the pathological changes in vascular intimal hyperplasia in MMD. 8,9…”