450 - Pathobiology of True Arteriovenous Malformations

Abstract

Cerebrovascular malformations are classified based on their histopathologic features: arteriovenous malformation (AVM), venous angioma, cavernous malformation, and capillary telangiectasia. True AVMs are abnormalities of the intracranial vessels that consist of a number of direct connections between the arterial and venous systems without an intervening capillary bed. AVMs are sporadic or syndromic in origin, with sporadic AVMs being more common with a global prevalence of 0.04% to 0.52%. Mixed cerebrovascular lesions that include AVMs are rare, the most common association being mixed cerebrovascular lesions with developmental venous anomalies. Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant vascular dysplasia affecting multiple organ systems. Symptomatic brain AVMs occur in 5% of patients with HHT, and asymptomatic lesions in 13%. HHT results from mutations in ENG (HHT1) or ACVRL1 (HHT2) and rarely SMAD4, all genes involved in TGF-β superfamily signaling. Research suggests a role for variants of HHT genes mutated in sporadic brain AVMs. AVMs are now considered dynamic lesions and undergo active angiogenesis and vascular remodeling throughout life. This concept is opening a new clinical paradigm in which pharmacologic interventions are proposed to stabilize these abnormal blood vessels and prevent further growth or hemorrhage. Bone morphogenetic protein/transforming growth factor β and vascular endothelial growth factor/vascular endothelial growth factor receptor signaling play a significant role in brain AVM pathogenesis. Somatic activating mutations in the KRAS gene have been identified as a cause of AVM. Next-generation sequencing has detected a high prevalence of KRAS/BRAF (87.1%) mutations in brain AVMs. Future therapies could be developed to specifically inhibit the Ras/Raf pathway. Anticancer agents already in clinical use could be repurposed to treat brain AVMs. Future developments may lead to the development of novel pharmaceutical agents, which may enhance the therapeutic effects or reduce the morbidity from existing treatments or perhaps even eliminate the need for direct intervention completely.