Advances in the Genetics and Molecular Biology of Brain Arteriovenous Malformations

Brain arteriovenous malformations (bAVMs) are high-flow vascular lesions characterized by direct arteriovenous shunting without an intervening capillary bed. The identification of somatic KRAS and BRAF mutations in sporadic bAVM endothelial cells (ECs) has fundamentally reshaped current understanding of bAVM biology, indicating that activation of the RAS/MAPK pathway drives aberrant angiogenic programs. In parallel, advances in genomic technologies have led to recognition of bAVMs as dynamic lesions that undergo ongoing vascular remodeling. Comprehensive transcriptomic profiling, including single-cell RNA sequencing, has uncovered distinctive molecular signatures in bAVM ECs, including heightened angiogenic and inflammatory signaling, endothelial-to-mesenchymal transition–like features, and loss of normal arteriovenous identity. Furthermore, animal models with EC-specific expression of mutant KRAS or BRAF exhibit bAVM-like lesions, which support the hypothesis that hyperactivation of the RAS/MAPK pathway is a key driver of lesion formation. These insights have accelerated the development of mechanism-based therapeutic strategies, and MEK and BRAF inhibitors targeting the RAS/MAPK pathway have shown promising results in preclinical studies. However, clinical translation remains challenging because of low variant allele frequencies and limited access to lesional tissue for genetic testing. Future approaches combining minimally invasive sampling methods, such as endovascular biopsy and peripheral blood cell-free DNA analysis, with ultra-sensitive detection technologies are expected to help overcome these limitations. Taken together, accumulating genetic evidence and a growing understanding of the inflammatory and immune microenvironment provide an important foundation not only for a deeper understanding of bAVM pathobiology but also for the development of future targeted therapies.