Pathogenic mechanism of extracranial arteriovenous malformations: insights from clinical, pathological, and genetic analyses.

Extracranial arteriovenous malformations (AVMs) are rare aggressive vascular malformations, and half of AVMs harbor mutations in the RAS/RAF/MAPK pathway. AVMs consist of abnormal networks of small vessels formed between arteries and veins. Although the abnormal small-vessel networks are considered to cause AVM progression, the underlying mechanisms remain poorly understood. This study elucidated the mechanisms underlying the pathogenesis of extracranial AVM in relation to genetic mutations. This retrospective clinical, pathological, and genetic study included 30 patients with extracranial AVMs. MAP2K1, KRAS, and BRAF mutations were identified in 14 (46.7%), 1 (3.3%), and 1 (3.3%) patient(s), respectively. Mutant AVMs were predominant in females, and histologically showed more infantile hemangioma-like small vessels and more enlarged small vessels inside the perineurium. Immunohistochemistry revealed high expression levels of phosphorylated ERK (extracellular signal regulated kinases), a downstream effector of the RAS/RAF/MAPK pathway, in AVMs regardless of mutational status or vessel type. Spatial transcriptomics revealed upregulation of genes involved in "positive regulation of cell adhesion", "positive regulation of cell migration" and "blood vessel development" in the abnormal small vessels in MAP2K1-mutant AVMs. Among the up-regulated genes, MAP4K4, which regulates pathological angiogenesis and is a therapeutic target, was highly expressed in abnormal small vessels in AVMs. This study reports significant genotype-phenotype correlations in AVMs, indicating gene-specific effects. A detailed analysis of gene-specific effects, focusing especially on abnormal small-vessel networks, may offer insights into the mechanisms underlying AVM pathogenesis and its implications for targeted therapies.