Transcriptomic Profiling of Intracranial Arteries in Adult Patients With Moyamoya Disease Reveals Novel Insights Into Its Pathogenesis

Abstract

Moyamoya disease (MMD) is a rare, progressively steno-occlusive cerebrovascular disorder of unknown etiology. Here, we revealed the gene expression profile of the intracranial arteries in MMD via the RNA-sequencing (RNA-seq). We identified 556 differentially expressed genes (DEGs) for MMD, including 449 and 107 significantly upregulated or downregulated genes. Compared with atherosclerosis-associated intracranial artery stenosis/occlusion (AS-ICASO) controls, upregulated genes were mainly involved in extracellular matrix (ECM) organization, whereas downregulated genes were primarily associated with mitochondrial function and oxidative phosphorylation in MMD. Moreover, we found that a separate sex analysis uncovers more DEGs (n = 1.022) compared to an combined sex analysis in MMD. We identified 133 and 439 sex-specific DEGs for men and women in MMD, respectively. About 95.6% of sex-specific DEGs were protein-coding genes and 3% of the genes belonged to long non-coding RNAs (lncRNA). Sex-specific DEGs were observed on all chromosomes, of which 95.49 and 96.59% were autosomal genes in men and women, respectively. These sex-specific DEGs, such as aquaporin-4 (AQP4), superoxide dismutase 3 (SOD3), and nuclear receptor subfamily 4 group A member 1 (NR4A1), may contribute to sex differences in MMD. This transcriptomic study highlighted that ECM and mitochondrial function are the central molecular mechanisms underlying MMD, and revealed sex differences in the gene expression in the intracranial arteries, thereby providing new insights into the pathogenesis of MMD.

The Progression of Pathophysiology of Moyamoya Disease

“…More studies using intracranial vessel samples should be delivered in the future. 64 In the follow-up studies, continuous investigations into genetic, angiogenic, and inflammatory factors will contribute to a deeper understanding of the etiology and pathogenesis of MMD and provide novel and effective inchoate diagnostic and therapeutic targets for MMD. This might ultimately be conducive to delaying or reversing the progression of the disease.…”

“…Similarly, our previous work has found that patients with MMD exhibited significantly higher expression of MMP-2 and TIMP-1 in MCA specimens. 64 MMPs were elevated after RNF213 silencing in ECs, indicating that RNF213 negatively controls the expressions of MMPs. 65 These results suggested that the disrupted balance between MMPs and TIMPs may be involved in the MMD pathophysiology through regulating ECM.…”

“…Several NFAT target genes, such as MMP-2 and MMP-9, are upregulated in patients with MMD. 42,64,73 Proinflammatory cytokines, such as Tumor Necrosis Factor-α (TNF-α) and IFN-γ, have been shown to activate RNF213 transcription in ECs by the AKT/protein kinase R pathway and proteintyrosine phosphatase-1B (PTP1B). 65 Noticeably, PTP1B suppressed RNF213 E3 ligase activity and controlled nonmitochondrial oxygen consumption and α-KG-dependent dioxygenases in breast cancer cells during hypoxia.…”

Increase of Circulating Endothelial Progenitor Cells and Released Angiogenic Factors in Children with Moyamoya Arteriopathy

“…The importance of sex differences in MMA are also reported in a transcriptomic profiling of ICA in adult patients. The study identified 133 and 439 sex-specific differentially expressed genes (DEGs) for men and women through an RNA sequencing (RNAseq) analysis [ 44 ]. Another RNAseq study identified a total of 533 DEGs in the peripheral blood of MMA patients, further highlighting the importance of a transcriptomic approach in a multifactorial disease [ 45 ].…”

“…Matrix metalloproteinase 9 (MMP-9) has an important role in extracellular matrix remodeling and angiogenesis regulation, and it is the main enzyme in the degradation of extracellular matrix proteins. It has been already reported as an important factor in MMA [ 42 , 43 , 44 , 45 ]. Interleukin 6 (IL-6) is a soluble mediator with a pleiotropic effect on inflammation, immune response, and hematopoiesis [ 46 ].…”