Recent Advances in Basic Research for Brain Arteriovenous Malformation

Abstract

Arteriovenous malformations (AVMs) are abnormal connections of vessels that shunt blood directly from arteries into veins. Rupture of brain AVMs (bAVMs) can cause life-threatening intracranial bleeding. Even though the majority of bAVM cases are sporadic without a family history, some cases are familial. Most of the familial cases of bAVMs are associated with a genetic disorder called hereditary hemorrhagic telangiectasia (HHT). The mechanism of bAVM formation is not fully understood. The most important advances in bAVM basic science research is the identification of somatic mutations of genes in RAS-MAPK pathways. However, the mechanisms by which mutations of these genes lead to AVM formation are largely unknown. In this review, we summarized the latest advance in bAVM studies and discussed some pathways that play important roles in bAVM pathogenesis. We also discussed the therapeutic implications of these pathways.

Recent progress understanding pathophysiology and genesis of brain AVM—a narrative review

“…About 5% of brain AVMs are linked to a genetic disorder, Hereditary Hemorrhagic Telangiectasia (HHT, Rendu-Osler-Weber Syndrome), which is an autosomal dominant vascular disease that affects approximately 1 in 5000 people worldwide [3]. The major clinical feature of HHT is hemorrhage from AVMs in multiple organs, including the brain.…”

“…Although clinical presentations are indistinguishable between HHT1 and HHT2, genotype-phenotype correlation studies have shown that HHT1 has a higher prevalence of AVMs in the brain and lungs, while HHT2 has a higher prevalence of AVMs in the liver and gastrointestinal tract. Brain AVMs are present in 10-16% of patients with HHT [3,37]. HHT1 patients have a significantly higher brain AVM prevalence (13%) compared with HHT2 patients (< 3%).…”

“…Recent studies have shown that blockages for both Bone Morphogenic Protein BMP9 and BMP10 could induce AVM development in the retinal vasculature, but it is not entirely clear whether both BMP9 and BMP10 are needed for ENG-ALK1 signaling. Nishida analyzed the prevalence of genetic variants in HHT and the correlations to phenotype in 171 patients with HHT and brain AVMs [3]. Twenty-seven percent of patients had a history of cerebral hemorrhage.…”

“…For the focal development of AVM, an additional local factor must be postulated. Right side: in sporadic AVM cases, somatic activating mutations in genes KRAS, BRAF, or MAP2K1 increase the level of MEK and pERK, leading to AVM development [3] and collaborators induced Smad4 deletion in mice at neonatal and adult stages, and looked for hemorrhage and the presence of aberrant arteriovenous connections in various organs [25]. Neonatal Smad4-deleted mice exhibited signs of gastrointestinal bleeding and AVM s in the brain, retina, nose, and intestine.…”

“…In contrast to these assumptions, recent evidence suggests that germline and somatic mutations are crucial for AVM development and that aberrant angiogenesis might be the key mechanism (Fig. 1) [3,53].…”