The brain is a highly vascularized structure - an estimated 600 km of capillary vessels - and dysfunction can be devastating. First described in the mid-1800s, brain arteriovenous malformations (AVMs) is a rare disease, consisting of a nest of abnormal arteries and veins and an absence of a capillary bed. AVMs can lead to serious neurological consequences such as seizures, migraines, or hemorrhage. Treatment varies in invasiveness from observation, embolization, radiosurgery, surgical resection, or to a hybrid of these, requiring months to years with increasing patient stress and hemorrhage risk.
AVM disease biology remains unclear, hindering improvements in diagnosis and treatment. Our goal is to highlight advances from the laboratory to the clinic and to suggest where gaps remain. We also intend to place AVMs in the context of neurovascular development and the complex interactions of cell types within the vasculature and the brain.
We aim to emphasize progress:
Toward Understanding the Microenvironment and Mechanisms:
The blood vessels and the myriad of cell types in the brain share an intimate relationship during development, in adults, and in disease. Within the neurovascular unit (NVU), endothelial cells (ECs), pericytes, neurons, astrocytes, microglia, smooth muscle cells, together with a complex basement membrane, interact to establish the blood-brain barrier (BBB) and normal brain function. What are the precise consequences when proper signals from surrounding tissues and vasculature are modified or missing, and in what way is this contributing to AVM disease? Mechanistic insight into the pathogenesis of AVMs has focused on Notch, SMADs, VEGF, TGFß, BMPs, KRAS, microRNAs, and somatic mutations, among others. There is likely no singular driver of the pathology, but rather a complex interplay amongst these mechanisms.
Toward the Development of Models:
Numerous AVM models exist in zebrafish, rodents, and cell culture; however, fewer human-based models are available. Multidimensional cell models, and vascularized brain organoid and iPSC technologies have the possibility to expand research tools. Improved imaging also has the potential to model AVM flow and BBB leakage.
Toward Molecular Classification:
Given the broad range of vascular anomalies in the brain, molecular classification is crucial to understanding AVMs and to targeted treatment. Brain AVMs are predominantly sporadic but also occur as a component in Hereditary Hemorrhagic Telangiectasia (HHT). Are HHT AVMs molecularly similar to sporadic AVMs, converging on a similar pathology? Are sporadic AVMs molecularly different according to flow rates or location in the brain? Organizations such as the International Society for the Study of Vascular Anomalies and the Brain Vascular Malformation Consortium aim to provide a platform for such discussion and discovery.
Toward Advancing Diagnosis and Treatment:
Diagnosis usually follows the presentation of symptoms, although AVMs are also found incidentally. What are the molecular determinants of hemorrhagic risk to guide treatment? Can improved diagnostic imaging evaluate this? Current treatments often have detrimental effects on tissue, highlighting the need for novel anti-angiogenesis and vascular targeting therapies.
We invite focused reviews, original research articles, novel models or imaging methods, hypotheses/theories, and insight/opinion articles.
The brain is a highly vascularized structure - an estimated 600 km of capillary vessels - and dysfunction can be devastating. First described in the mid-1800s, brain arteriovenous malformations (AVMs) is a rare disease, consisting of a nest of abnormal arteries and veins and an absence of a capillary bed. AVMs can lead to serious neurological consequences such as seizures, migraines, or hemorrhage. Treatment varies in invasiveness from observation, embolization, radiosurgery, surgical resection, or to a hybrid of these, requiring months to years with increasing patient stress and hemorrhage risk.
AVM disease biology remains unclear, hindering improvements in diagnosis and treatment. Our goal is to highlight advances from the laboratory to the clinic and to suggest where gaps remain. We also intend to place AVMs in the context of neurovascular development and the complex interactions of cell types within the vasculature and the brain.
We aim to emphasize progress:
Toward Understanding the Microenvironment and Mechanisms:
The blood vessels and the myriad of cell types in the brain share an intimate relationship during development, in adults, and in disease. Within the neurovascular unit (NVU), endothelial cells (ECs), pericytes, neurons, astrocytes, microglia, smooth muscle cells, together with a complex basement membrane, interact to establish the blood-brain barrier (BBB) and normal brain function. What are the precise consequences when proper signals from surrounding tissues and vasculature are modified or missing, and in what way is this contributing to AVM disease? Mechanistic insight into the pathogenesis of AVMs has focused on Notch, SMADs, VEGF, TGFß, BMPs, KRAS, microRNAs, and somatic mutations, among others. There is likely no singular driver of the pathology, but rather a complex interplay amongst these mechanisms.
Toward the Development of Models:
Numerous AVM models exist in zebrafish, rodents, and cell culture; however, fewer human-based models are available. Multidimensional cell models, and vascularized brain organoid and iPSC technologies have the possibility to expand research tools. Improved imaging also has the potential to model AVM flow and BBB leakage.
Toward Molecular Classification:
Given the broad range of vascular anomalies in the brain, molecular classification is crucial to understanding AVMs and to targeted treatment. Brain AVMs are predominantly sporadic but also occur as a component in Hereditary Hemorrhagic Telangiectasia (HHT). Are HHT AVMs molecularly similar to sporadic AVMs, converging on a similar pathology? Are sporadic AVMs molecularly different according to flow rates or location in the brain? Organizations such as the International Society for the Study of Vascular Anomalies and the Brain Vascular Malformation Consortium aim to provide a platform for such discussion and discovery.
Toward Advancing Diagnosis and Treatment:
Diagnosis usually follows the presentation of symptoms, although AVMs are also found incidentally. What are the molecular determinants of hemorrhagic risk to guide treatment? Can improved diagnostic imaging evaluate this? Current treatments often have detrimental effects on tissue, highlighting the need for novel anti-angiogenesis and vascular targeting therapies.
We invite focused reviews, original research articles, novel models or imaging methods, hypotheses/theories, and insight/opinion articles.
