Emerging pathogenic mechanisms in human brain arteriovenous malformations: a contemporary review in the multiomics era

Abstract

A variety of pathogenic mechanisms have been described in the formation, maturation, and rupture of brain arteriovenous malformations (bAVMs). While the understanding of bAVMs has largely been formulated based on animal models of rare hereditary diseases in which AVMs form, a new era of “omics” has permitted large-scale examinations of contributory genetic variations in human sporadic bAVMs. New findings regarding the pathogenesis of bAVMs implicate changes to endothelial and mural cells that result in increased angiogenesis, proinflammatory recruitment, and breakdown of vascular barrier properties that may result in hemorrhage; a greater diversity of cell populations that compose the bAVM microenvironment may also be implicated and complicate traditional models. Genomic sequencing of human bAVMs has uncovered inherited, de novo, and somatic activating mutations, such as KRAS, which contribute to the pathogenesis of bAVMs. New droplet-based, single-cell sequencing technologies have generated atlases of cell-specific molecular derangements. Herein, the authors review emerging genomic and transcriptomic findings underlying pathologic cell transformations in bAVMs derived from human tissues. The application of multiple sequencing modalities to bAVM tissues is a natural next step for researchers, although the potential therapeutic benefits or clinical applications remain unknown.

Peripheral macrophages in the development and progression of structural cerebrovascular pathologies

“…Brain AVMs are masses of abnormal vessels characterized by direct connections between arteries and veins without intervening capillaries that aggregate into a nidus and associated perinidal networks. 76 These lesions can be composed of single or multiple compartments and include numerous feeding arteries and draining veins. 77 The majority of bAVMs are congenital and are thought to arise in the 4th–8th week of embryonic development – the period during which the potential boundary of the vascular malformation is defined – with the ultimate angioarchitecture of the bAVM determined by cellular and molecular interactions throughout develpoment.…”

“…82 The growth and progression of bAVMs involves chronic interplay between endothelial cells, smooth muscle cells, pericytes, and peripheral leukocytes. 76 Interactions between leukocytes and the vessel wall during bAVM growth and hemorrhage have recently provided new insights into bAVM biology. 83 Clinically, approximately 50% of symptomatic bAVMs present hemorrhagically, 20–45% with seizures, and the remaining with headaches, neurological deficits, or incidentally.…”

Arteriovenous Malformations: An Update on Models and Therapeutic Targets

“…The majority of familial AVM cases (about 5% of all AVM cases) are associated with hereditary hemorrhagic telangiectasia (HHT) and capillary malformation-arteriovenous malformation syndrome, both of which are autosomal dominant inherited genetic conditions. [27,28]) Preclinical investigations have attempted to isolate the genes that lead to cerebral AVM in these diseases. It has been shown that congenital mutations in the TGF-β and RAS vascular signaling pathways result in an increased risk of cerebral AVM formation [29,30].…”

“…It has been shown that congenital mutations in the TGF-β and RAS vascular signaling pathways result in an increased risk of cerebral AVM formation [29,30]. This research has primarily been focused on the genes that code for Endoglin (ENG) and Activin A receptor type II-like 1 (ALK1) [27,28,31]. About 95% of AVM cases are not related to familial conditions [32].…”

Multi-omics analysis reveals GABAergic dysfunction after traumatic brainstem injury in rats

“…In recent years, multi-omics technologies including genomics, transcriptomics, metabolomics, and proteomics have been widely used to explore the mechanisms of various diseases ( Ohashi et al, 2015 ), including but not limited to Alzheimer’s disease, human brain arteriovenous malformation, and other brain diseases ( Wang et al, 2021 ; Winkler et al, 2022 ). In a previous study, Zhong et al (2016) used transcriptomic techniques to observe changes of mRNA and lncRNA expression in the cortex of TBI model mice.…”