Review of treatment and therapeutic targets in brain arteriovenous malformation

Pan, Peipei; Weinsheimer, Shantel; Cooke, Daniel L; Winkler, Ethan A.; Abla, Adib A.; Kim, Helen; Su, Hua

doi:10.1177/0271678x211026771

Cited by 24 publications

(14 citation statements)

References 145 publications

(191 reference statements)

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“…In previous monoculture and animal models, MEKi has been investigated as a possible treatment strategy 5,7,22,48,49 . In monocultures, MEKi re-established VE-cadherin to cell junctions and restored normal actin localization and cell shape by suppressing ERK phosphorylation 5 .…”

Section: Discussionmentioning

confidence: 99%

Development and characterization of a human model of arteriovenous malformation (AVM)-on-a-chip

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et al. 2022

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Brain arteriovenous malformations (AVMs) are a disorder where abnormal, enlarged blood vessels connect arteries directly to veins, without an intervening capillary bed. AVMs are one of the leading causes of hemorrhagic stroke in children and young adults. Most human sporadic brain AVMs are associated with genetic activating mutations in the KRAS gene. Our goal was to develop an in vitro model of human AVMs using human endothelial cells harbouring a clinically relevant KRAS mutation in a dynamic microfluidic culture system to enable vessel formation and perfusion to capture key morphological structure and barrier dysfunction characteristics of AVM. Using a combination of normal and KRAS4AG12V mutated endothelial cells (ECs), we demonstrated that vessels formed by KRAS4AG12V ECs were significantly wider and more leaky than vascular beds formed by wild-type ECs, recapitulating key structural and functional hallmarks of AVMs. Immunofluorescence staining revealed a breakdown of adherens junctions in mutant KRAS vessels only, leading to increased permeability of the vessel network. Furthermore, treatment with a MEK inhibitor, but not a PI3K inhibitor, resulted in an improvement in endothelial barrier function (decreased permeability) without affecting vessel width. Here, we have demonstrated the ability to create human KRAS-dependent AVM-like vessels in vitro in a self-assembling microvessel platform that is amenable to drug testing.

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Section: Discussionmentioning

confidence: 99%

Development and characterization of a human model of arteriovenous malformation (AVM)-on-a-chip

Soon

et al. 2022

Preprint

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“…A key future step in the improvement of the clinical management of brain AVMs would be the development of novel anti-angiogenic therapies 336 , 337 , for instance targeting the pathways downstream of KRAS mutations with MEK inhibitors (which are already approved for the treatment of brain tumours 338 , 339 ) or other targets emanating from single-cell studies 75 , 163 , 265 . For explorations of the future clinical and pharmacological treatment of brain AVMs, we refer readers to recent reviews on this topic 336 , 337 .…”

Section: Angiogenesis In Brain Avmsmentioning

confidence: 99%

Shaping the brain vasculature in development and disease in the single-cell era

et al. 2023

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The CNS critically relies on the formation and proper function of its vasculature during development, adult homeostasis and disease. Angiogenesis — the formation of new blood vessels — is highly active during brain development, enters almost complete quiescence in the healthy adult brain and is reactivated in vascular-dependent brain pathologies such as brain vascular malformations and brain tumours. Despite major advances in the understanding of the cellular and molecular mechanisms driving angiogenesis in peripheral tissues, developmental signalling pathways orchestrating angiogenic processes in the healthy and the diseased CNS remain incompletely understood. Molecular signalling pathways of the ‘neurovascular link’ defining common mechanisms of nerve and vessel wiring have emerged as crucial regulators of peripheral vascular growth, but their relevance for angiogenesis in brain development and disease remains largely unexplored. Here we review the current knowledge of general and CNS-specific mechanisms of angiogenesis during brain development and in brain vascular malformations and brain tumours, including how key molecular signalling pathways are reactivated in vascular-dependent diseases. We also discuss how these topics can be studied in the single-cell multi-omics era.

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“…Recent research has contributed to delineating the processes involved in bAVM development, progression, and bleeding (95). The RAS/MAPK/ERK signaling pathway is a common route with peripheral AVMs, and the recent finding of somatic gene mutations in bAVMs has added to the growing list of significant signaling pathways involved in bAVM and isolated potential targets to stabilize vascular tissue thereby decreasing the risk of spontaneous ICH (96). In mice specific model, treated with bevacizumab or trastuzumab, Walker et al reported reduction in dysplastic vessels (97).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Endovascular Management of Brain Arteriovenous Malformations

et al. 2023

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Due to the risk of cerebral hemorrhage, and its related morbidity-mortality, brain arteriovenous malformations (bAVM) are a rare and threatening disease. Concerning bAVM management, only one randomized control trial -the ARUBA trial -has been published so far. The results of the ARUBA trial favor a non-interventional approach in the case of an unruptured bAVM, however implementation of these findings is challenging in daily practice.Instead, management relies on multidisciplinary discussions that lead to patient-specific strategies based on local expertise and experience in reference centers. Given the wide patterns of presentation and multiple treatment modalities recommendations are also difficult to follow. Endovascular treatment (EVT) is a widely used modality which can be used for curative treatment, or prior to surgery or radiosurgery ("pre-EVT"). EVT practice is in constant evolution (i.e. venous approach, combination with surgery during the same anesthesia, etc.). Liquid embolic agents (LEA) such as ethylene vinyl alcohol (EVOH) copolymer and cyanoacrylates (CYA), and their method of injection to increase bAVM occlusion, have also benefited from technical evolutions such as the use of adjunctive flow arrest techniques (mini balloons, pressure cooker technique and multiple catheters). Further research is necessary to evaluate the advantages and disadvantages of EVT.

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Review of treatment and therapeutic targets in brain arteriovenous malformation

Cited by 24 publications

References 145 publications

Development and characterization of a human model of arteriovenous malformation (AVM)-on-a-chip

Development and characterization of a human model of arteriovenous malformation (AVM)-on-a-chip

Shaping the brain vasculature in development and disease in the single-cell era

Endovascular Management of Brain Arteriovenous Malformations

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