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

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

doi:https://doi.org/10.1007/s00428-025-04158-7

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

Hirose, Katsutoshi; Hori, Yumiko; Maruyama, Kazuaki et al.

Virchows Archiv, 2025

Number of Access:35（2025-09-07 14:30 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/102597

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Title	Pathogenic mechanism of extracranial arteriovenous malformations: insights from clinical, pathological, and genetic analyses
Creator	NRID 1000000824898 1000000824898 ORCID 0000-0003-4148-1106 0000-0003-4148-1106 researchmap permalink -hirose -hirose Scopus Author ID 57190276392 57190276392 CreatorName Hirose, Katsutoshi
	NRID 1000060528785 1000060528785 researchmap permalink yhhori yhhori CreatorName Hori, Yumiko
	NRID 1000090821984 1000090821984 CreatorName Maruyama, Kazuaki
	NRID 1000010636830 1000010636830 researchmap permalink daisukem daisukem Scopus Author ID 35315737900 35315737900 CreatorName Motooka, Daisuke
	NRID 1000080444496 1000080444496 ORCID 0000-0003-4367-9343 0000-0003-4367-9343 researchmap permalink read0107167 read0107167 Scopus Author ID 8952419300 8952419300 CreatorName Hata, Kenji
	NRID 1000020792584 1000020792584 ORCID 0000-0001-6134-3275 0000-0001-6134-3275 researchmap permalink s_tahara s_tahara Scopus Author ID 57189030096 57189030096 CreatorName Tahara, Shinichiro
	NRID 1000050747037 1000050747037 ORCID 0000-0002-6753-1688 0000-0002-6753-1688 researchmap permalink takahiromatsui takahiromatsui Scopus Author ID 35176152500 35176152500 CreatorName Matsui, Takahiro
	NRID 1000040528791 1000040528791 ORCID 0000-0002-5124-0026 0000-0002-5124-0026 researchmap permalink snojima snojima Scopus Author ID 16224082000 16224082000 CreatorName Nojima, Satoshi
	NRID 1000000379257 1000000379257 ORCID 0009-0006-7636-5833 0009-0006-7636-5833 CreatorName Kohara, Masaharu
	NRID 1000000242967 1000000242967 CreatorName Imanaka-Yoshida, Kyoko
	NRID 1000030243249 1000030243249 ORCID 0000-0002-0338-0251 0000-0002-0338-0251 researchmap permalink osteobone0729 osteobone0729 Scopus Author ID 7003411866 7003411866 CreatorName Toyosawa, Satoru
	NRID 1000010283772 1000010283772 ORCID 0000-0001-8490-3650 0000-0001-8490-3650 researchmap permalink read0046454 read0046454 Scopus Author ID 7003914326 7003914326 CreatorName Morii, Eiichi
Subject	Arteriovenous malformation
	BRAF
	KRAS
	MAP2K1
	MAP4K4
	Spatial transcriptomics
Description	The version of record of this article, first published in Virchows Archiv, is available online at Publisher’s website: https://doi.org/10.1007/s00428-025-04158-7.
Abstract	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.
Publisher	Springer Science and Business Media Deutschland GmbH
Source Title	Virchows Archiv
Date of Issued	2025-07-02
Language	English
Handle URL	https://hdl.handle.net/11094/102597
PISSN	09456317
eISSN	14322307
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1007/s00428-025-04158-7
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Virchows Archiv. 2025
DC.title	Pathogenic mechanism of extracranial arteriovenous malformations: insights from clinical, pathological, and genetic analyses
DC.creator	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
DC.publisher	Springer Science and Business Media Deutschland GmbH
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-07-02
DC.identifier	https://doi.org/10.1007/s00428-025-04158-7
DC.subject	Arteriovenous malformation
	BRAF
	KRAS
	MAP2K1
	MAP4K4
	Spatial transcriptomics
DC.description	The version of record of this article, first published in Virchows Archiv, is available online at Publisher’s website: https://doi.org/10.1007/s00428-025-04158-7.
DCTERMS.abstract	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.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	102597
citation_title	Pathogenic mechanism of extracranial arteriovenous malformations: insights from clinical, pathological, and genetic analyses
citation_author	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
citation_publisher	Springer Science and Business Media Deutschland GmbH
citation_language	English
citation_date	2025-07-02
citation_journal_title	Virchows Archiv
citation_doi	https://doi.org/10.1007/s00428-025-04158-7
citation_public_url	https://hdl.handle.net/11094/102597

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

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