Decoding brain arteriovenous malformations: from genetic insights to modeling the vascular maze

Brain arteriovenous malformations (bAVMs) are complex cerebrovascular anomalies characterized by a tangle of dysplastic vessels, including feeding arteries, a nidus, and draining veins, with the absence of an intervening capillary bed. bAVMs pose a significant risk of severe complications, such as intracranial hemorrhage, seizures, and progressive neurological deficits, leading to substantial morbidity and mortality. While advancements in treatments, including microsurgical resection, endovascular embolization, and stereotactic radiosurgery, have improved patient outcomes, the underlying pathogenesis of bAVMs remains poorly understood. The emergence of next-generation sequencing (NGS) has identified critical genetic mutations implicated in bAVMs, such as KRAS and BRAF, which dysregulate the MAPK signaling pathway. Additionally, hereditary forms of bAVMs, including those associated with hereditary hemorrhagic telangiectasia (HHT), are linked to mutations in TGF-β signaling pathway genes, such as ENG and ALK1. These discoveries have spurred the development of genetically engineered animal models (GEAMs) that faithfully recapitulate key pathological features of bAVMs, including vascular dysplasia, arteriovenous shunting, and intracranial hemorrhage. However, traditional surgical hemodynamic models and current GEAMs have limitations, particularly in replicating the spontaneous onset and progression of bAVMs or capturing the role of the perivascular microenvironment in disease development. This review evaluates the strengths and limitations of existing bAVM models, emphasizing their contributions to understanding the hemodynamic, molecular, and cellular mechanisms underlying bAVM pathogenesis. Emerging trends, such as advanced imaging, transcriptomic analyses, and patient-derived induced pluripotent stem cells, offer new avenues for studying bAVM development and progression. By integrating diverse modeling strategies and advancing translational efforts, innovative diagnostic and therapeutic approaches can be developed. This review aims to guide researchers in selecting appropriate models and fostering a deeper understanding of bAVMs, ultimately improving patient care.