Genetics helps untangle the causes behind a rare and complex vascular disorder

Osaka, Japan – Our genes underlie all aspects of life, from our looks to how our cells behave. This includes diseases, as genetic changes can underlie the development and progression of certain health problems. This is true for arteriovenous malformations (AVMs), vascular anomalies that are known to be life-threatening. However, the biological mechanisms driving their growth have remained unclear, until now.

AVMs are tangled clusters of abnormal blood vessels that can cause pain, bleeding, and even heart failure. While they can occur anywhere in the body, those found outside the brain, termed “extracranial AVMs”, are particularly complex and invasive. These AVMs often require surgery and have high rates of recurrence.

Now, recent findings from The University of Osaka, published in Virchows Archiv: European Journal of Pathology, have found and analyzed genes to help pave the way for new and targeted AVM therapies.

“We analyzed tissue samples from 30 patients, representing the world’s largest number of extracranial AVM cases subjected to genetic analysis together,” says Katsutoshi Hirose, first author. “We hoped to find information that could help us define the mechanism behind the disease in relation to genetic mutations.”

They found that nearly half of the patients carried mutations in the RAS/RAF/MAPK signaling pathway, which controls how cells grow and communicate. These mutations were linked to the characteristic abnormal vascular morphology and were frequently detected in younger female patients.

Through analysis of the causative genes, RNA, proteins, clinical findings, and the tissue pathology, the team discovered that the small, tangled vessels (called the nidus) within the AVMs exhibited increased activity in certain genes. One gene in particular, MAP4K4, was highly expressed in the nidus and may play a key role in AVM development. MAP4K4 ordinarily regulates cell movement and blood vessel growth. The researchers suggest the gene may thus also be responsible for the pathological angiogenesis of AVMs.

Intriguingly, ERK, a downstream effector of the RAS/RAF/MAPK signaling pathway, exhibited increased activity in all AVM cases – including in those without detectable mutations. “Clinical trials involving inhibitors of this signaling pathway are already underway internationally and may provide a promising new direction for AVM treatment,” explains Yumiko Hori, senior author.

With few effective treatments, no known cure and a high likelihood of recurrence, these findings offer new hope. The study highlights the potential for effective precision therapies to treat AVMs without invasive surgery.

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The article, “Pathogenic Mechanism of Extracranial Arteriovenous Malformations: Insights from Clinical, Pathological, and Genetic Analyses”, was published in Virchows Archiv: European Journal of Pathology at DOI: https://doi.org/10.1007/s00428-025-04158-7.

About The University of Osaka
The University of Osaka was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, The University of Osaka is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation. 
Website: https://resou.osaka-u.ac.jp/en