Neurovascular inflammation in the pathogenesis of brain arteriovenous malformations

Abstract

Brain arteriovenous malformations (bAVM) arise as congenital or sporadic focal lesions with a significant risk for intracerebral hemorrhage (ICH). A wide range of interindividual differences is present in the onset, progression, and severity of bAVM. A growing body of gene expression and polymorphism‐based research studies support the involvement of localized inflammation in bAVM disease progression and rupture. In this review article, we analyze the altered responses of neural, vascular, and immune cell types that contribute to the inflammatory process, which exacerbates the pathophysiological progression of vascular dysmorphogenesis in bAVM lesions. The cumulative effect of inflammation in bAVM development is orchestrated by various genetic moderators and inflammatory mediators. We also discuss the potential therapies for the treatment of brain AVM by targeting the inflammatory processes and mediators. Elucidating the precise role of inflammation in the bAVM growth and hemorrhage would open novel avenues for noninvasive and effectual causal therapy that may complement the current therapeutic strategies.

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

“…Comparable to intracranial aneurysms, inflammatory processes have been suspected for years to have a potential influence for the development and rupture of arteriovenous malformations [26,30,31,33,55]. The advent of ferumoxytol-enhanced and later gadolinium-enhanced Black Blood MRI (BbMRI) allowed us to visualize contrast leak as a surrogate of inflammation [8,42].…”

“…With nine AVMs classified into the high rupture risk group (six of them hemorrhagic) and seven into the low rupture risk group, the observed venous-to-arterial time-to-peak ratio was significantly lower in the high rupture risk and hemorrhagic groups. Kumar and colleagues compared computer flow simulation with MRA for evaluating AVM hemodynamics [26,27,28]. Mean flow in defined vessels, diameter, and pressure were compared between modeling results and validation measurements using special flow software, showing that modeling results and measurements were matching with a small deviation.…”

Cellular loci involved in the development of brain arteriovenous malformations

“…Among those genes that are involved in EC arteriovenous specification, abnormal NOTCH signaling has been detected in human bAVMs and both gain or loss of function of Notch in mouse lead to bAVM formation ( Murphy et al, 2009 ; ZhuGe et al, 2009 ; Li et al, 2014 ). Although ECs have been identified as the primary cellular locus for AVM initiation ( Walker et al, 2011b ; Choi et al, 2012 ; Garrido-Martin et al, 2014 ; Park H. et al, 2021 ; Shaligram et al, 2021 ), other cellular loci, such as pericytes and microglia/macrophages, have also been shown to play roles in bAVM pathogenesis ( Chen et al, 2013a ; Zhang et al, 2016a ; Winkler et al, 2018 ; Krithika and Sumi, 2021 ; Scherschinski et al, 2022 ). Both human and mouse bAVM vessels have less mural cell coverage than normal vessels, which is associated with vessel leakage and hemorrhage ( Chen et al, 2013a ; Winkler et al, 2018 ).…”

Spontaneous subarachnoid hemorrhage due to arteriovenous malformation mimicking migraine: A case report

“…Arteriovenous malformation (AVM) is one of the causes of SAH that is rare but very important to be identified and treated immediately, mainly because AVM rupture has a risk of rebleeding up to 20% [2] . AVM is an abnormal blood vessel (nidus) that drains blood directly from arteries to veins without passing through the capillary system [2] .…”

“…Arteriovenous malformation (AVM) is one of the causes of SAH that is rare but very important to be identified and treated immediately, mainly because AVM rupture has a risk of rebleeding up to 20% [2] . AVM is an abnormal blood vessel (nidus) that drains blood directly from arteries to veins without passing through the capillary system [2] . Because of the high risk of rebleeding and the rapid emergency progression, identifying patients with AVM-associated SAH is essential, significantly to differentiate them from other diseases with similar symptoms.…”