Hirose Katsutoshi, Hori Yumiko, Maruyama Kazuaki, Motooka Daisuke, Hata Kenji, Tahara Shinichiro, Matsui Takahiro, Nojima Satoshi, Kohara Masaharu, Imanaka-Yoshida Kyoko, Toyosawa Satoru, Morii Eiichi
Department of Oral and Maxillofacial Pathology, The University of Osaka Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Department of Pathology, The University of Osaka Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Virchows Arch. 2025 Jul 2. doi: 10.1007/s00428-025-04158-7.
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.
颅外动静脉畸形（AVM）是罕见的侵袭性血管畸形，其中一半的AVM在RAS/RAF/MAPK通路中存在突变。AVM由动脉和静脉之间形成的异常小血管网络组成。尽管这些异常的小血管网络被认为会导致AVM进展，但其潜在机制仍知之甚少。本研究阐明了与基因突变相关的颅外AVM发病机制。这项回顾性临床、病理和基因研究纳入了30例颅外AVM患者。分别在14例（46.7%）、1例（3.3%）和1例（3.3%）患者中检测到MAP2K1、KRAS和BRAF突变。突变型AVM在女性中占主导地位，组织学上显示出更多婴儿血管瘤样小血管以及神经束膜内更多扩张的小血管。免疫组化显示，无论突变状态或血管类型如何，RAS/RAF/MAPK通路的下游效应物磷酸化ERK（细胞外信号调节激酶）在AVM中均高表达。空间转录组学显示，MAP2K1突变型AVM异常小血管中参与“细胞黏附的正调控”“细胞迁移的正调控”和“血管发育”的基因上调。在这些上调基因中，调节病理性血管生成且为治疗靶点的MAP4K4在AVM异常小血管中高表达。本研究报告了AVM中显著的基因型-表型相关性，表明存在基因特异性效应。对基因特异性效应进行详细分析，尤其是关注异常小血管网络，可能为AVM发病机制及其对靶向治疗的意义提供见解。
