Materiały źródłowe

• #1 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8396465/

  Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. […] The lack of FDA approved medical treatments for AVMs reflects our limited understanding of the pathogenesis of AVMs, in particular how AVMs develop and progress. Mounting evidence suggests that even for familial AVMs, underlying genetic defects in the germline alone might not be sufficient for AVMs to manifest. Local events such as somatic mutations and pro-angiogenic stimuli might be additionally required drivers. […] Insights from experimental animal models employing cell-specific deletions of causative genes suggest the endothelial cell (EC) as the key cell type in AVM formation.

• #2 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://www.mdpi.com/1422-0067/22/16/9037

  Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. Therapeutic approaches are limited, and AVMs can cause significant morbidity and mortality. Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. […] The lack of FDA approved medical treatments for AVMs reflects our limited understanding of the pathogenesis of AVMs, in particular how AVMs develop and progress. Mounting evidence suggests that even for familial AVMs, underlying genetic defects in the germline alone might not be sufficient for AVMs to manifest. Local events such as somatic mutations and pro-angiogenic stimuli might be additionally required drivers.

• #3 Arteriovenous malformation – Wikipedia

  https://en.wikipedia.org/wiki/Arteriovenous_malformation

  An arteriovenous malformation (AVM) is an abnormal connection between arteries and veins, bypassing the capillary system. […] An AVM interferes with this process by forming a direct connection of the arteries and veins, bypassing the capillary bed. […] As an AVM lacks the dampening effect of capillaries on the blood flow, the AVM can get progressively larger over time as the amount of blood flowing through it increases, forcing the heart to work harder to keep up with the extra blood flow. […] The resulting tangle of blood vessels, often called a nidus, has no capillaries. […] It can be extremely fragile and prone to bleeding because of the abnormally direct connections between high-pressure arteries and low-pressure veins.

• #4 Arteriovenous malformation – Wikipedia

  https://en.wikipedia.org/wiki/Arteriovenous_malformation

  An arteriovenous malformation (AVM) is an abnormal connection between arteries and veins, bypassing the capillary system. […] An AVM interferes with this process by forming a direct connection of the arteries and veins, bypassing the capillary bed. […] As an AVM lacks the dampening effect of capillaries on the blood flow, the AVM can get progressively larger over time as the amount of blood flowing through it increases, forcing the heart to work harder to keep up with the extra blood flow. […] The resulting tangle of blood vessels, often called a nidus, has no capillaries. […] It can be extremely fragile and prone to bleeding because of the abnormally direct connections between high-pressure arteries and low-pressure veins.

• #5 Brain arteriovenous malformations – UpToDate

  https://www.uptodate.com/contents/brain-arteriovenous-malformations

  Arteriovenous malformations (AVMs) are the most dangerous of the cerebrovascular malformations with the potential to cause intracranial hemorrhage and epilepsy in many cases. […] The pathogenesis of brain AVMs is not well understood. Traditionally, brain AVMs were considered sporadic congenital developmental vascular lesions, but this notion has been disputed by many well-documented reports of de novo brain AVM formation. […] Genetic variation may influence brain AVM development and clinical course. […] The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu syndrome), an autosomal dominant condition. […] The angioarchitecture of brain AVMs is direct arterial to venous connections without an intervening capillary network. […] Aneurysms can be a source of bleeding in patients with brain AVMs and are thought to worsen their prognosis. […] Abnormal flow and a vascular steal phenomenon have been suggested to underlie some clinical symptoms associated with brain AVMs.

• #6

  https://scite.ai/reports/10.3390/ijms22169037

  Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). […] Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. […] Such continued stimulation increases the risk of hemorrhage and bleeding, deteriorated flow can cause blood steal phenomena, and the circulation of high-flow blood creates a relatively hypoxic environment in the proximal tissues at the AVM site. […] Arteriovenous malformation (AVM) is characterized by high-flow blood vessels connecting arteries and veins without capillaries. This disease shows increased angiogenesis and a pathophysiological hypoxic environment in proximal tissues.

• #7 Arteriovenous malformation – Wikipedia

  https://en.wikipedia.org/wiki/Arteriovenous_malformation

  An arteriovenous malformation (AVM) is an abnormal connection between arteries and veins, bypassing the capillary system. […] An AVM interferes with this process by forming a direct connection of the arteries and veins, bypassing the capillary bed. […] As an AVM lacks the dampening effect of capillaries on the blood flow, the AVM can get progressively larger over time as the amount of blood flowing through it increases, forcing the heart to work harder to keep up with the extra blood flow. […] The resulting tangle of blood vessels, often called a nidus, has no capillaries. […] It can be extremely fragile and prone to bleeding because of the abnormally direct connections between high-pressure arteries and low-pressure veins.

• #8

  https://link.springer.com/article/10.1007/s10143-021-01526-0

  Considerable progress has been made over the past years to better understand the genetic nature and pathophysiology of brain AVM. […] Whole-genome sequencing clarified the genetic origin of sporadic and familial AVM to a large degree, although some open questions remain. […] Substantial progress has been made towards understanding the embryology of brain AVM. […] In contrast to arterial aneurysms, complete modeling of the intranidal flow and a thorough understanding of the mechanical properties of the AVM nidus are still lacking at the present time. […] There is little doubt that AVM are of dysembryological nature. […] Recent evidence suggests that germline and somatic mutations are crucial for AVM development and that aberrant angiogenesis might be the key mechanism. […] 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.

• #9 Brain arteriovenous malformations – UpToDate

  https://www.uptodate.com/contents/brain-arteriovenous-malformations

  Arteriovenous malformations (AVMs) are the most dangerous of the cerebrovascular malformations with the potential to cause intracranial hemorrhage and epilepsy in many cases. […] The pathogenesis of brain AVMs is not well understood. Traditionally, brain AVMs were considered sporadic congenital developmental vascular lesions, but this notion has been disputed by many well-documented reports of de novo brain AVM formation. […] Genetic variation may influence brain AVM development and clinical course. […] The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu syndrome), an autosomal dominant condition. […] The angioarchitecture of brain AVMs is direct arterial to venous connections without an intervening capillary network. […] Aneurysms can be a source of bleeding in patients with brain AVMs and are thought to worsen their prognosis. […] Abnormal flow and a vascular steal phenomenon have been suggested to underlie some clinical symptoms associated with brain AVMs.

• #10

  https://link.springer.com/article/10.1007/s10143-021-01526-0

  HHT has been considered a disease caused by defects in the signaling of TGF- family members. […] The RAS/MAPK/ERK cascade couples signals from cell surface receptors to transcription factors, which regulate gene expression. […] It has been shown that alteration of the RAS-MAPK pathway triggers the development of tumors. […] Summarizing these genetic analyses, it can be concluded that sporadic AVM are consequences of local somatic mutations affecting the endothelium. […] Comparable to intracranial aneurysms, inflammatory processes have been suspected for years to have a potential influence for the development and rupture of arteriovenous malformations. […] The results point to involvement of inflammatory mediators, loss of cerebrovascular quiescence, and impaired integrity of the vascular wall in the pathophysiology of brain AVMs. […] The relation of inflammation and flow pattern and to the risk of hemorrhage remains incompletely understood.

• #11 Understanding the role of miRNAs in the pathogenesis of brain arteriovenous malformations

  https://www.techscience.com/biocell/v46n1/44748/html

  The pathogenesis of JP-HHT might be due to different effects of lowered levels of mothers against decapentaplegic homolog 4 (SMAD4) within endothelial cells, leading to decreased transforming growth factor beta/bone morphogenetic proteins (TGF-/BMPs) signaling, which may produce vascular dysplasia. […] Disturbances in endothelial signaling contribute to the development of arteriovenous malformations, and the NOTCH and TGF- pathways appear to be particularly important for the development of these lesions. […] Currently, there is no doubt that an important role in the development and pathogenesis of cerebrovascular diseases play miRNAs. […] The results of these studies allow a better understanding of the processes associated with the formation and rupture of brain AVMs. […] In addition, we suggested that circulating miRNAs would function as novel non-invasive biomarkers for brain AVMs, but which still needs further research.

• #12

  https://www.jci.org/articles/view/172837

  In the context of AVMs, VEGF assumes a crucial role in both development and growth. […] Elevated VEGF levels in the brains of mice with ALK1 deficiency-induced AVMs have also been linked to increased AVM-related hemorrhage rates and mortality, suggesting that VEGF is not only involved in AVM development, but also in subsequent complications. […] The majority of AVMs arise sporadically as isolated lesions. In these noninherited AVMs, the important MAPK signaling cascade plays a crucial and pathogenic role. […] In extracranial AVMs, somatic mutations in MAP2K1, encoding MEK1, have been detected in 64% of patients. […] Experimental studies utilizing mouse models have provided compelling evidence supporting the role of activated KRAS within ECs in the development of AVMs across various soft tissues, including the brain, liver, and heart. […] The unraveling of the major initiating mechanisms for AVM formation has propelled the field to think of targeted molecular therapies that could be used alone or as pre-, peri-, and postinterventional procedures.

• #13 Development and characterization of a human model of arteriovenous malformation (AVM)-on-a-chip | bioRxiv

  https://www.biorxiv.org/content/10.1101/2022.01.20.477166v2.full-text

  Brain arteriovenous malformations (AVMs) are a disorder wherein 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. By generating human endothelial cells harboring a clinically relevant mutation found in most human patients (activating mutations within the small GTPase KRAS) and seeding them in a dynamic microfluidic cell culture system that enables vessel formation and perfusion, we demonstrate that vessels formed by KRAS4A^G12V mutant endothelial cells (ECs) were significantly wider and more leaky than vascular beds formed by wild-type ECs, recapitulating key structural and functional hallmarks of human AVM pathogenesis. Immunofluorescence staining revealed a breakdown of adherens junctions in mutant KRAS vessels only, leading to increased vascular permeability, a hallmark of hemorrhagic stroke. Various mutations within genes encoding proteins in the mitogen-activated protein kinase (MAPK/ERK, e.g. the RAS-RAF-MEK-ERK) pathway have been implicated in AVM pathology. Recently, somatic activating KRAS mutations in endothelial cells (ECs) have been reported in as many as 50% of clinical samples. This is thought to increase the permeability of the vessel wall, and to leave vessels prone to hemorrhage. Although these genetic mutations are sufficient for the development of AVM in zebrafish and mouse models, the initiation, development, and remodelling of these dynamic vessel malformations are influenced by factors in the microenvironment. Specifically, vascular endothelial growth factor (VEGF) and other pro-angiogenic factors are highly expressed in AVMs, leading to increased vessel permeability and susceptibility to rupture. Other pathways, such as Notch and transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) have also been implicated in AVM regulation, particularly with discontinuity of cell-cell junctions and cell proliferation, resulting in vascular dysplasia and instability. Moreover, growing evidence suggests that the AVM microenvironment may promote AVM growth. Inflammation driven by local macrophages and reduction of pericyte coverage have been described as contributing factors in AVM pathogenesis, as they promote excessive angiogenic responses. Additionally, a high flow rate is a defining feature in AVMs that leads to a positive feedback loop to increase local vessel enlargement in high-velocity vessels. However, there is limited knowledge as to how environmental cues from surrounding cells, hemodynamics, and the KRAS mutation contribute to the pathogenesis of AVMs.

• #14

  https://link.springer.com/article/10.1007/s00439-023-02605-6

  Brain arteriovenous malformation (BAVM) is a rare but serious cerebrovascular disease whose pathogenesis has not been fully elucidated. Studies have found that epigenetic regulation, genetic variation and their signaling pathways, immune inflammation, may be the cause of BAVM the main reason. […] Studies have found that epigenetic regulation such as DNA methylation, non-coding RNAs and m6A RNA modification can regulate endothelial cell proliferation, apoptosis, migration and damage repair of vascular malformations through different target gene pathways. Gene defects such as KRAS, ACVRL1 and EPHB4 lead to a disordered vascular environment, which may promote abnormal proliferation of blood vessels through ERK, NOTCH, mTOR, Wnt and other pathways. […] Recent single-cell sequencing data revealed the diversity of various cell types within BAVM, as well as the heterogeneous expression of vascular-associated antigens, while neutrophils, macrophages and cytokines such as IL-6, IL-1, TNF-, and IL-17A in BAVM tissue were significantly increased. […] Therefore, further studies on molecular biological mechanisms will help to gain insight into the pathogenesis of BAVM and develop potential therapeutic strategies.

• #15 Frontiers | Cellular loci involved in the development of brain arteriovenous malformations

  https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2022.968369/full

  The mechanism of bAVM development is not fully understood and there is no specific medical therapy available for bAVM patients. […] Mouse model studies identified several key factors that are crucial for bAVM initiation and progression. Angiogenesis and AVM causative gene mutation in endothelial cells (ECs) are necessary for AVM development. […] 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. […] Although ECs have been identified as the primary cellular locus for AVM initiation, other cellular loci, such as pericytes and microglia/macrophages, have also been shown to play roles in bAVM pathogenesis. […] Inflammation may promote bAVM progression.

• #16

  https://scholars.duke.edu/individual/pub1646147

  Pediatric arteriovenous malformations (AVMs) are rare but carry a risk of devastating neurological morbidity and mortality. […] The complex etiology of pediatric AVMs persists as an impediment to a comprehensive understanding of pathogenesis and subsequent targeted gene therapies. […] The Ephrin B2/EphB4 (RASA-1, KRAS, and MEK) signaling axis, hemorrhagic telangiectasia, NOTCH, and TIE2 receptor complexes (PIK3CA and mTOR), in addition to other isolated gene variants, have been implicated in AVM pathogenesis. […] Furthering the understanding of the molecular mechanisms of AVM pathogenesis will lead to future novel therapies and treatment paradigms.

• #17 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8396465/

  In familial AVMs, the question of why AVMs arise in seemingly random anatomic locations in an individual carrying the allele with the causative germline gene mutation within every cell has been a conundrum. A three-event hypothesis suggesting concurrence of two additional, regionally confined triggers, is mainly based on insights gained from animal studies. […] These studies suggested that a combination of a loss of one functional allele in an HHT-locus, a local loss of protein, and an angiogenic stimulus directed towards ECs might be required for AVM development in mice. […] Furthermore, determinants such as blood flow and shear stress have been identified to be contributory to AVM formation.

• #18 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://www.mdpi.com/1422-0067/22/16/9037

  A possible explanation for this phenomenon might be found in studies showing that increased flow in a microvascular bed can cause capillaries to transition to arterioles. […] The three steps of AVM development identified above were also described in patients with pulmonary AVMs (PAVMs) in HHT using high resolution CT scanning. […] In familial AVMs, the question of why AVMs arise in seemingly random anatomic locations in an individual carrying the allele with the causative germline gene mutation within every cell has been a conundrum. […] Furthermore, determinants such as blood flow and shear stress have been identified to be contributory to AVM formation. […] Further research will be required to strengthen our understanding of AVM formation, and translate these insights from animal models to humans.

• #19 Pathogenesis of Brain Arteriovenous Malformations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4908075/

  It is known that higher levels of angiogenic factors and inflammatory cytokines are observed in bAVMs than in the normal brain tissues. […] From insights into these current bAVM models, it is suggested that both angiogenic stimulation (environmental factors) and regional conditional homozygous gene deletion (genetic predisposition) may promote the ideal bAVM development in the adult mouse brain. […] Although pathogenesis of bAVMs is not clearly understood, many researches are underway, especially using HHT animal models.

• #20 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8396465/

  Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. […] The lack of FDA approved medical treatments for AVMs reflects our limited understanding of the pathogenesis of AVMs, in particular how AVMs develop and progress. Mounting evidence suggests that even for familial AVMs, underlying genetic defects in the germline alone might not be sufficient for AVMs to manifest. Local events such as somatic mutations and pro-angiogenic stimuli might be additionally required drivers. […] Insights from experimental animal models employing cell-specific deletions of causative genes suggest the endothelial cell (EC) as the key cell type in AVM formation.

• #21 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://www.mdpi.com/1422-0067/22/16/9037

  Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. Therapeutic approaches are limited, and AVMs can cause significant morbidity and mortality. Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. […] The lack of FDA approved medical treatments for AVMs reflects our limited understanding of the pathogenesis of AVMs, in particular how AVMs develop and progress. Mounting evidence suggests that even for familial AVMs, underlying genetic defects in the germline alone might not be sufficient for AVMs to manifest. Local events such as somatic mutations and pro-angiogenic stimuli might be additionally required drivers.

• #22 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8396465/

  Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. […] The lack of FDA approved medical treatments for AVMs reflects our limited understanding of the pathogenesis of AVMs, in particular how AVMs develop and progress. Mounting evidence suggests that even for familial AVMs, underlying genetic defects in the germline alone might not be sufficient for AVMs to manifest. Local events such as somatic mutations and pro-angiogenic stimuli might be additionally required drivers. […] Insights from experimental animal models employing cell-specific deletions of causative genes suggest the endothelial cell (EC) as the key cell type in AVM formation.

• #23 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://www.mdpi.com/1422-0067/22/16/9037

  Insights from experimental animal models employing cell-specific deletions of causative genes suggest the endothelial cell (EC) as the key cell type in AVM formation. […] Over the last decades, it has become increasingly clear that causative mutations, either somatic or germline, in a single AVM are causing gene results in a complex interplay between multiple cellular pathways. […] To develop novel effective therapeutic strategies for AVM treatment, a better understanding of the pathogenesis of AVM formation is paramount. Hypotheses on how AVMs form and evolve are still a matter of debate and are based on clinical observations employing different imaging modalities as well as on identification of molecular, genetic, and cellular key-player in affected tissues of humans and experimental animals.

• #24 Novel Brain Arteriovenous Malformation Mouse Models for Type 1 Hereditary Hemorrhagic Telangiectasia | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088511

  We have also shown that endothelial homozygous Eng deletion is required for the development of the HHT1 brain AVM phenotype, whereas deletion of Eng in macrophages is insufficient. […] The prevailing view regarding AVM manifestation in HHT is that it is caused by haploinsufficiency of one of its causative genes. However, ENG haploinsufficiency in endothelial cells in human HHT lesions appears to be insufficient for AVM development. We found that Eng homozygous deletion in endothelial cells seems to be required for brain AVM formation. […] Therefore, deletion of Eng in microphages alone is not sufficient for brain AVM formation.

• #25 Arteriovenous malformation Map2k1 mutation affects vasculogenesis | Scientific Reports

  https://www.nature.com/articles/s41598-023-35301-6

  The transcriptome changes in MAP2K1 expressing ECs provides insights into the mechanisms that contribute to AVM formation. […] Our results showing that the Map2k1 mutation in ECs affects vasculogenesis genes and pathways contributes to our understanding of AVMs pathogenesis. […] The activating MAP2K1 EC mutation may cause AVM enlargement through abnormal blood vessel production that secondarily causes overgrowth of tissues. […] Drugs that inhibit EC migration, adhesion, and angiogenesis may prove beneficial to patients with AVMs.

• #26 Arteriovenous Malformation MAP2K1 Mutation Causes Local Cartilage Overgrowth by a Cell-Non Autonomous Mechanism | Scientific Reports

  https://www.nature.com/articles/s41598-020-61444-x

  Extracranial arteriovenous malformation (AVM) is most commonly caused by MAP2K1 mutations in the endothelial cell. […] The mechanism by which AVMs cause overgrowth of involved tissues is unknown. […] Our data shows that only the vascularized tissue adjacent to cartilage of auricular AVM contains somatic MAP2K1 mutations; the underlying overgrown cartilage does not. Consequently, the enlargement of cartilage does not result directly from a mutation in the cartilage (cell-autonomous). Instead, cartilage hypertrophy occurs secondarily to its surrounding soft tissue containing a vasculature with mutant MAP2K1 endothelial cells (cell-non autonomous). […] We predict that other major vascular malformations (capillary, lymphatic, venous) cause overgrowth of tissues by a similar cell-non autonomous mechanism as AVM.

• #27 Pathogenesis of Brain Arteriovenous Malformations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4908075/

  It is known that higher levels of angiogenic factors and inflammatory cytokines are observed in bAVMs than in the normal brain tissues. […] From insights into these current bAVM models, it is suggested that both angiogenic stimulation (environmental factors) and regional conditional homozygous gene deletion (genetic predisposition) may promote the ideal bAVM development in the adult mouse brain. […] Although pathogenesis of bAVMs is not clearly understood, many researches are underway, especially using HHT animal models.

• #28

  https://www.jci.org/articles/view/172837

  In the context of AVMs, VEGF assumes a crucial role in both development and growth. […] Elevated VEGF levels in the brains of mice with ALK1 deficiency-induced AVMs have also been linked to increased AVM-related hemorrhage rates and mortality, suggesting that VEGF is not only involved in AVM development, but also in subsequent complications. […] The majority of AVMs arise sporadically as isolated lesions. In these noninherited AVMs, the important MAPK signaling cascade plays a crucial and pathogenic role. […] In extracranial AVMs, somatic mutations in MAP2K1, encoding MEK1, have been detected in 64% of patients. […] Experimental studies utilizing mouse models have provided compelling evidence supporting the role of activated KRAS within ECs in the development of AVMs across various soft tissues, including the brain, liver, and heart. […] The unraveling of the major initiating mechanisms for AVM formation has propelled the field to think of targeted molecular therapies that could be used alone or as pre-, peri-, and postinterventional procedures.

• #29 Cerebral arteriovenous malformations. Part 1: cellular and molecular biology in: Neurosurgical Focus Volume 26 Issue 5 (2009) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/26/5/article-pE10.xml

  The growth potential of AVMs and their regression may involve opposing forces supporting or inhibiting angiogenesis and vascular remodeling. A phenomenon noted in tumor angiogenesis is the need for both VEGF and ANG-2; if VEGF is absent, vessels will undergo regression if ANG-2 is present. […] The roles of the TGF family in vascular development are complex and multidimensional; for example, TGF is biphasic. In the early stages of development, TGF inhibits vascular endothelial proliferation; in later stages, it promotes the differentiation of surrounding mesenchymal cells to differentiate into pericytes and SMCs. […] The expression of VEGF is high in the endothelial layer and media of vessels in AVMs. Pathological studies have shown that almost three-quarters of AVMs resected following incomplete embolization express VEGF and Flk-1, whereas the endothelium of only one-quarter of AVMs not preoperatively embolized expresses these factors. This finding may explain why partially obliterated AVMs recur. […] The activation of this pathway signals SMC proliferation, which contributes to the vascular remodeling and growth/regression of these lesions.

• #30 The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

  https://www.mdpi.com/2227-9059/11/11/2876

  The treatment of symptomatic bAVMs, whether as a part of a complex inherited genetic syndrome (such as HHT), or as an isolated sporadic lesion initiated by a somatic variant within the endothelium (e.g., KRAS gain of function), represents an incredible challenge for neurosurgical teams, due to the fragility of intracranial vessels and the associated risk of stroke and hemorrhage. […] The decision for intervention is patient-specific and depends on bAVM eloquence, size, location, vascular anatomy, and complexity, as well as hemorrhage history. […] Currently no FDA-approved drug therapies exist for treating bAVM, although efforts are focused on the use of FDA-approved MEK1/2 inhibitors, as the MAPK kinase cascade (RAF-MEK-ERK) is an obligate target of KRAS in the endothelium. […] With limited treatment options for these patients, there is an urgent need to identify novel therapeutic targets based on our current understanding of bAVM pathogenesis.

• #31 Understanding the role of miRNAs in the pathogenesis of brain arteriovenous malformations

  https://www.techscience.com/biocell/v46n1/44748/html

  Understanding the molecular basis of pathogenesis, timely diagnosis, and treatment of brain AVMs are some of the urgent problems in neurosurgery. […] Recent studies have shown that miRNAs can be involved in brain AVMs formation and rupture. […] Recent studies indicate that miRNAs are involved in the formation and rupture of brain AVMs, which gives us new insights into the pathogenesis of brain AVMs and might lead to the finding of new therapeutic targets. […] According to some studies, heterozygous loss-of-function mutations in the RAS P21 protein activator 1 (RASA1) gene can cause a pathology such as capillary malformation, which is a recently discovered, familial disorder in which patients have cutaneous capillary malformations, but they can also be located in the brain. […] RASA1 mutations also link the pathogenesis of brain AVMs to extracellular signal-regulated kinase (ERK) signaling, as RAS is upstream of ERK and diminished RAS deactivation engenders increased ERK activity.

• #32 Frontiers | Cellular loci involved in the development of brain arteriovenous malformations

  https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2022.968369/full

  The mechanism of bAVM development is not fully understood and there is no specific medical therapy available for bAVM patients. […] Mouse model studies identified several key factors that are crucial for bAVM initiation and progression. Angiogenesis and AVM causative gene mutation in endothelial cells (ECs) are necessary for AVM development. […] 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. […] Although ECs have been identified as the primary cellular locus for AVM initiation, other cellular loci, such as pericytes and microglia/macrophages, have also been shown to play roles in bAVM pathogenesis. […] Inflammation may promote bAVM progression.

• #33

  https://insight.jci.org/articles/view/125940

  Arteriovenous malformations (AVMs) are high-flow lesions directly connecting arteries and veins. […] Patients with AVMs exhibit reduced coverage of the vessels by pericytes, the mural cells of microvascular capillaries; however, the mechanism underlying this pericyte reduction and its association with AVM pathogenesis remains unknown. […] We hypothesized that Notch signaling in pericytes is crucial to maintain pericyte homeostasis and prevent AVM formation. […] Overall, our findings reveal a mechanism of AVM formation and highlight the Notch signaling pathway as an essential mediator in this process. […] Our findings show how the deficiency of Notch signaling in pericytes results in increased pericyte apoptosis and decrease in pericyte coverage of the vasculature, ultimately leading to the formation of AVMs.

• #34 Cerebral arteriovenous malformations. Part 1: cellular and molecular biology in: Neurosurgical Focus Volume 26 Issue 5 (2009) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/26/5/article-pE10.xml

  The growth potential of AVMs and their regression may involve opposing forces supporting or inhibiting angiogenesis and vascular remodeling. A phenomenon noted in tumor angiogenesis is the need for both VEGF and ANG-2; if VEGF is absent, vessels will undergo regression if ANG-2 is present. […] The roles of the TGF family in vascular development are complex and multidimensional; for example, TGF is biphasic. In the early stages of development, TGF inhibits vascular endothelial proliferation; in later stages, it promotes the differentiation of surrounding mesenchymal cells to differentiate into pericytes and SMCs. […] The expression of VEGF is high in the endothelial layer and media of vessels in AVMs. Pathological studies have shown that almost three-quarters of AVMs resected following incomplete embolization express VEGF and Flk-1, whereas the endothelium of only one-quarter of AVMs not preoperatively embolized expresses these factors. This finding may explain why partially obliterated AVMs recur. […] The activation of this pathway signals SMC proliferation, which contributes to the vascular remodeling and growth/regression of these lesions.

• #35 Understanding the role of miRNAs in the pathogenesis of brain arteriovenous malformations

  https://www.techscience.com/biocell/v46n1/44748/html

  The pathogenesis of JP-HHT might be due to different effects of lowered levels of mothers against decapentaplegic homolog 4 (SMAD4) within endothelial cells, leading to decreased transforming growth factor beta/bone morphogenetic proteins (TGF-/BMPs) signaling, which may produce vascular dysplasia. […] Disturbances in endothelial signaling contribute to the development of arteriovenous malformations, and the NOTCH and TGF- pathways appear to be particularly important for the development of these lesions. […] Currently, there is no doubt that an important role in the development and pathogenesis of cerebrovascular diseases play miRNAs. […] The results of these studies allow a better understanding of the processes associated with the formation and rupture of brain AVMs. […] In addition, we suggested that circulating miRNAs would function as novel non-invasive biomarkers for brain AVMs, but which still needs further research.

• #36 Cerebral arteriovenous malformations. Part 1: cellular and molecular biology in: Neurosurgical Focus Volume 26 Issue 5 (2009) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/26/5/article-pE10.xml

  The growth potential of AVMs and their regression may involve opposing forces supporting or inhibiting angiogenesis and vascular remodeling. A phenomenon noted in tumor angiogenesis is the need for both VEGF and ANG-2; if VEGF is absent, vessels will undergo regression if ANG-2 is present. […] The roles of the TGF family in vascular development are complex and multidimensional; for example, TGF is biphasic. In the early stages of development, TGF inhibits vascular endothelial proliferation; in later stages, it promotes the differentiation of surrounding mesenchymal cells to differentiate into pericytes and SMCs. […] The expression of VEGF is high in the endothelial layer and media of vessels in AVMs. Pathological studies have shown that almost three-quarters of AVMs resected following incomplete embolization express VEGF and Flk-1, whereas the endothelium of only one-quarter of AVMs not preoperatively embolized expresses these factors. This finding may explain why partially obliterated AVMs recur. […] The activation of this pathway signals SMC proliferation, which contributes to the vascular remodeling and growth/regression of these lesions.

• #37 Pathology Outlines – Hemangioma & variants

  https://www.pathologyoutlines.com/topic/softtissuehemangioma.html

  Specific pathogenesis has not been fully understood. […] Currently regarded as a multifactorial condition, resulting in endothelial proliferation, with uncontrolled angiogenesis and abnormal function of downstream pathways (notably HIF1α, VEGF and PI3K / Akt). […] RASA1 mutations: arteriovenous malformations, Klippel-Trenaunay syndrome, Sturge-Weber syndrome, Parker-Weber syndrome. […] GNAQ mutation: Sturge-Weber syndrome. […] PDGFRβ and its downstream signaling pathways (PI3K / Akt / mTOR) are activated in infantile hemangioma.

• #38 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8396465/

  In familial AVMs, the question of why AVMs arise in seemingly random anatomic locations in an individual carrying the allele with the causative germline gene mutation within every cell has been a conundrum. A three-event hypothesis suggesting concurrence of two additional, regionally confined triggers, is mainly based on insights gained from animal studies. […] These studies suggested that a combination of a loss of one functional allele in an HHT-locus, a local loss of protein, and an angiogenic stimulus directed towards ECs might be required for AVM development in mice. […] Furthermore, determinants such as blood flow and shear stress have been identified to be contributory to AVM formation.

• #39 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://www.mdpi.com/1422-0067/22/16/9037

  A possible explanation for this phenomenon might be found in studies showing that increased flow in a microvascular bed can cause capillaries to transition to arterioles. […] The three steps of AVM development identified above were also described in patients with pulmonary AVMs (PAVMs) in HHT using high resolution CT scanning. […] In familial AVMs, the question of why AVMs arise in seemingly random anatomic locations in an individual carrying the allele with the causative germline gene mutation within every cell has been a conundrum. […] Furthermore, determinants such as blood flow and shear stress have been identified to be contributory to AVM formation. […] Further research will be required to strengthen our understanding of AVM formation, and translate these insights from animal models to humans.

• #40 Genetic and epigenetic mechanisms in the development of arteriovenous malformations in the brain | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-016-0248-8

  Vascular malformations are developmental congenital abnormalities of the vascular system which may involve any segment of the vascular tree such as capillaries, veins, arteries, or lymphatics. […] The causative factor and pathogenic mechanisms of AVMs are unknown. Importantly, no marker proteins have been identified for AVM. […] Altered local hemodynamics in the blood vessels can affect cellular metabolism and may trigger epigenetic factors of the endothelial cell. […] We propose that AVMs result from a series of changes in the DNA methylation and histone modifications in the genes connected to vascular development. […] Aberrant epigenetic modifications in the genome of endothelial cells may drive the artery or vein to an aberrant phenotype. […] This review focuses on the molecular pathways of arterial and venous development and discusses the role of hemodynamic forces in the development of AVM and possible link between hemodynamic forces and epigenetic mechanisms in the pathogenesis of AVM.

• #41 Genetic and epigenetic mechanisms in the development of arteriovenous malformations in the brain | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-016-0248-8

  The causes for development of AVMs in the human brain are still elusive. It is widely speculated that altered hemodynamic forces at the junction of an artery and a vein might provoke the development of AVM and hemodynamic forces may be the critical epigenetic regulator in deciding the endothelial fate. […] All existing studies suggest that the abrupt changes in the hemodynamic flow in the junction of arteriovenous blood vessels might strongly influence the epigenetic mediators and eventually lead to the development of AVM. […] Thus, we speculate the presence of aberrant epigenetic landscape in AVM, particularly acquired mutations in epigenetic proteins and alterations of DNA methylations in the promoters of vascular developmental specific pathway genes. […] A detailed study of the epigenetic signals of genes associated with vascular development pathways could throw light on the genetic and epigenetic mechanisms in the development of AVMs.

• #42 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://www.mdpi.com/1422-0067/22/16/9037

  A possible explanation for this phenomenon might be found in studies showing that increased flow in a microvascular bed can cause capillaries to transition to arterioles. […] The three steps of AVM development identified above were also described in patients with pulmonary AVMs (PAVMs) in HHT using high resolution CT scanning. […] In familial AVMs, the question of why AVMs arise in seemingly random anatomic locations in an individual carrying the allele with the causative germline gene mutation within every cell has been a conundrum. […] Furthermore, determinants such as blood flow and shear stress have been identified to be contributory to AVM formation. […] Further research will be required to strengthen our understanding of AVM formation, and translate these insights from animal models to humans.

• #43 A comprehensive analysis of patients with cerebral arteriovenous malformation with headache: assessment of risk factors and treatment effectiveness | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-024-01774-7

  In this study, female gender, supply artery dilatation, and occipital lobe location were identified as potential risk factors for headaches in AVMs. In addition, microsurgery, stereotactic radiosurgery, and multimodal treatment showed significant benefits in headache relief compared to conservative treatment. […] This phenomenon may be attributable to hemodynamic alterations caused by AVM. In AVM, abnormal arteriovenous shunting causes blood to bypass the normal capillary network, thereby reducing blood supply to the surrounding normal brain tissue. Under such circumstances, dilation of the supply artery could further exacerbate local ischemia, triggering headaches. […] The association between headaches and various cerebrovascular ischemic diseases has been extensively reported. Activation of the trigeminovascular system is often considered a plausible explanation for the mechanism of headache in unruptured AVMs.

• #44 Brain arteriovenous malformations – UpToDate

  https://www.uptodate.com/contents/brain-arteriovenous-malformations

  Arteriovenous malformations (AVMs) are the most dangerous of the cerebrovascular malformations with the potential to cause intracranial hemorrhage and epilepsy in many cases. […] The pathogenesis of brain AVMs is not well understood. Traditionally, brain AVMs were considered sporadic congenital developmental vascular lesions, but this notion has been disputed by many well-documented reports of de novo brain AVM formation. […] Genetic variation may influence brain AVM development and clinical course. […] The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu syndrome), an autosomal dominant condition. […] The angioarchitecture of brain AVMs is direct arterial to venous connections without an intervening capillary network. […] Aneurysms can be a source of bleeding in patients with brain AVMs and are thought to worsen their prognosis. […] Abnormal flow and a vascular steal phenomenon have been suggested to underlie some clinical symptoms associated with brain AVMs.

• #45 The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

  https://www.mdpi.com/2227-9059/11/11/2876

  Brain arteriovenous malformations (bAVMs) are focal vascular lesions composed of abnormal vascular channels without an intervening capillary network. As a result, high-pressure arterial blood shunts directly into the venous outflow system. […] Critically, inflammation has been suggested to contribute to lesion progression. Here we summarize the current literature discussing the role of the immune system in bAVM pathogenesis and lesion progression, as well as the potential for targeting inflammation to prevent bAVM rupture and intracranial hemorrhage. […] Overall, this review addresses the etiology and pathogenesis of brain arteriovenous malformations from an endothelial-centric point of view, focusing on the interplay between endothelial dysfunction and immune cell dynamics and how their interplay impacts disease progression.

• #46

  https://link.springer.com/article/10.1007/s10143-021-01526-0

  HHT has been considered a disease caused by defects in the signaling of TGF- family members. […] The RAS/MAPK/ERK cascade couples signals from cell surface receptors to transcription factors, which regulate gene expression. […] It has been shown that alteration of the RAS-MAPK pathway triggers the development of tumors. […] Summarizing these genetic analyses, it can be concluded that sporadic AVM are consequences of local somatic mutations affecting the endothelium. […] Comparable to intracranial aneurysms, inflammatory processes have been suspected for years to have a potential influence for the development and rupture of arteriovenous malformations. […] The results point to involvement of inflammatory mediators, loss of cerebrovascular quiescence, and impaired integrity of the vascular wall in the pathophysiology of brain AVMs. […] The relation of inflammation and flow pattern and to the risk of hemorrhage remains incompletely understood.

• #47 The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

  https://www.mdpi.com/2227-9059/11/11/2876

  Specifically, recent scRNA-sequencing studies suggest that compromised BBB function, inferred from loss of mature CNS endothelial BBB markers and increased expression of peripheral endothelial genes, could lead to an influx of inflammatory cells that may drive bAVM rupture. […] The recruitment of monocyte-derived cell types, as well as the activation of resident CNS cells in the brain (e.g., microglia and astrocytes), combined with a flood of secreted proteolytic enzymes and barrier-disrupting cytokines and pro-angiogenic growth factors, together with the rise in reactive oxygen species, all act to promote vascular and basement membrane breakdown. […] In this sense, blocking monocyte homing to bAVM tissue may be a possible strategy to reduce bAVM severity, although studies are needed to confirm this, including using genetic mouse models of sporadic KRAS-dependent bAVMs.

• #48 The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

  https://www.mdpi.com/2227-9059/11/11/2876

  Specifically, recent scRNA-sequencing studies suggest that compromised BBB function, inferred from loss of mature CNS endothelial BBB markers and increased expression of peripheral endothelial genes, could lead to an influx of inflammatory cells that may drive bAVM rupture. […] The recruitment of monocyte-derived cell types, as well as the activation of resident CNS cells in the brain (e.g., microglia and astrocytes), combined with a flood of secreted proteolytic enzymes and barrier-disrupting cytokines and pro-angiogenic growth factors, together with the rise in reactive oxygen species, all act to promote vascular and basement membrane breakdown. […] In this sense, blocking monocyte homing to bAVM tissue may be a possible strategy to reduce bAVM severity, although studies are needed to confirm this, including using genetic mouse models of sporadic KRAS-dependent bAVMs.

• #49

  https://link.springer.com/article/10.1007/s00439-023-02605-6

  Brain arteriovenous malformation (BAVM) is a rare but serious cerebrovascular disease whose pathogenesis has not been fully elucidated. Studies have found that epigenetic regulation, genetic variation and their signaling pathways, immune inflammation, may be the cause of BAVM the main reason. […] Studies have found that epigenetic regulation such as DNA methylation, non-coding RNAs and m6A RNA modification can regulate endothelial cell proliferation, apoptosis, migration and damage repair of vascular malformations through different target gene pathways. Gene defects such as KRAS, ACVRL1 and EPHB4 lead to a disordered vascular environment, which may promote abnormal proliferation of blood vessels through ERK, NOTCH, mTOR, Wnt and other pathways. […] Recent single-cell sequencing data revealed the diversity of various cell types within BAVM, as well as the heterogeneous expression of vascular-associated antigens, while neutrophils, macrophages and cytokines such as IL-6, IL-1, TNF-, and IL-17A in BAVM tissue were significantly increased. […] Therefore, further studies on molecular biological mechanisms will help to gain insight into the pathogenesis of BAVM and develop potential therapeutic strategies.

• #50 The Role of Macrophage in the Pathogenesis of Brain Arteriovenous Malformation | Ma | International Journal of Hematology Research

  http://www.ghrnet.org/index.php/ijhr/article/view/1097

  Brain arteriovenous malformation (BAVM) is an important risk factor of intracranial hemorrhage, especially in children and young adults. Inflammation has been implicated in BAVM lesion progression. Among various inflammatory components, macrophage is one of the major inflammatory cells present in human ruptured and unruptured BAVM and in the BAVM lesions of animal models. The role of macrophage in BAVM pathogenesis is not fully understood. […] In this review, we summarize recent studies on macrophages and introduce a non-invasive imaging protocol as a potential tool for detecting macrophage in BAVM and predicting the risk of BAVM rupture.

• #51

  https://insight.jci.org/articles/view/125940

  Arteriovenous malformations (AVMs) are high-flow lesions directly connecting arteries and veins. […] Patients with AVMs exhibit reduced coverage of the vessels by pericytes, the mural cells of microvascular capillaries; however, the mechanism underlying this pericyte reduction and its association with AVM pathogenesis remains unknown. […] We hypothesized that Notch signaling in pericytes is crucial to maintain pericyte homeostasis and prevent AVM formation. […] Overall, our findings reveal a mechanism of AVM formation and highlight the Notch signaling pathway as an essential mediator in this process. […] Our findings show how the deficiency of Notch signaling in pericytes results in increased pericyte apoptosis and decrease in pericyte coverage of the vasculature, ultimately leading to the formation of AVMs.

• #52

  https://insight.jci.org/articles/view/125940

  Arteriovenous malformations (AVMs) are high-flow lesions directly connecting arteries and veins. […] Patients with AVMs exhibit reduced coverage of the vessels by pericytes, the mural cells of microvascular capillaries; however, the mechanism underlying this pericyte reduction and its association with AVM pathogenesis remains unknown. […] We hypothesized that Notch signaling in pericytes is crucial to maintain pericyte homeostasis and prevent AVM formation. […] Overall, our findings reveal a mechanism of AVM formation and highlight the Notch signaling pathway as an essential mediator in this process. […] Our findings show how the deficiency of Notch signaling in pericytes results in increased pericyte apoptosis and decrease in pericyte coverage of the vasculature, ultimately leading to the formation of AVMs.

• #53

  https://insight.jci.org/articles/view/125940

  Arteriovenous malformations (AVMs) are high-flow lesions directly connecting arteries and veins. […] Patients with AVMs exhibit reduced coverage of the vessels by pericytes, the mural cells of microvascular capillaries; however, the mechanism underlying this pericyte reduction and its association with AVM pathogenesis remains unknown. […] We hypothesized that Notch signaling in pericytes is crucial to maintain pericyte homeostasis and prevent AVM formation. […] Overall, our findings reveal a mechanism of AVM formation and highlight the Notch signaling pathway as an essential mediator in this process. […] Our findings show how the deficiency of Notch signaling in pericytes results in increased pericyte apoptosis and decrease in pericyte coverage of the vasculature, ultimately leading to the formation of AVMs.

• #54

  https://insight.jci.org/articles/view/125940

  This work sheds light into a potentially novel mechanism of AVM formation as a consequence of poor perivascular coverage and points to the Notch signaling pathway as a critical mediator in this process. […] Our data indicate that Notch signaling mediates pericyte survival through regulation of PDGFR levels.

• #55 Frontiers | Cellular loci involved in the development of brain arteriovenous malformations

  https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2022.968369/full

  Brain arteriovenous malformations (bAVMs) are abnormal vessels that are prone to rupture, causing life-threatening intracranial bleeding. The mechanism of bAVM formation is poorly understood. Nevertheless, animal studies revealed that gene mutation in endothelial cells (ECs) and angiogenic stimulation are necessary for bAVM initiation. Evidence collected through analyzing bAVM specimens of human and mouse models indicate that cells other than ECs also are involved in bAVM pathogenesis. Both human and mouse bAVMs vessels showed lower mural cell-coverage, suggesting a role of pericytes and vascular smooth muscle cells (vSMCs) in bAVM pathogenesis. Perivascular astrocytes also are important in maintaining cerebral vascular function and take part in bAVM development. Furthermore, higher inflammatory cytokines in bAVM tissue and blood demonstrate the contribution of inflammatory cells in bAVM progression, and rupture. The goal of this paper is to provide our current understanding of the roles of different cellular loci in bAVM pathogenesis.

• #56 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8396465/

  Over the last decades, it has become increasingly clear that causative mutations, either somatic or germline, in a single AVM are causing gene results in a complex interplay between multiple cellular pathways. […] To develop novel effective therapeutic strategies for AVM treatment, a better understanding of the pathogenesis of AVM formation is paramount. Hypotheses on how AVMs form and evolve are still a matter of debate and are based on clinical observations employing different imaging modalities as well as on identification of molecular, genetic, and cellular key-player in affected tissues of humans and experimental animals. […] A sequence of distinctive morphologic events was reported. First, there was dilatation of postcapillary venules, surrounded by a mononuclear infiltrate mainly consisting of lymphocytes. Next, luminal diameter and vascular wall thickness of venules increased, accompanied by recruitment of pericytes.

• #57 Cerebral arteriovenous malformations. Part 1: cellular and molecular biology in: Neurosurgical Focus Volume 26 Issue 5 (2009) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/26/5/article-pE10.xml

  The altered expression of up to 900 genes has been associated with AVMs. Perhaps 300 genes are upregulated and almost 560 are downregulated in cerebral vascular malformations. These genes encode growth factors, cell adhesion and ECM factors, inflammatory factors, MMPs, and endocrine hormones. […] The primitive capillary plexus has 3 basic characteristics. The surrounding mesenchymal cells migrate around the primitive capillary plexus and differentiate into SMCs and pericytes. As noted, there is programmed cell death to specific regions of the primitive capillary plexus, causing a remodeling of the vascular architecture. Finally, new branches form, and stabilization of the mature vascular structure occurs. The molecular aspects of vasculogenesis and angiogenesis are complex; however, aberrations of molecular signaling can lead to abnormal vascular development.

• #58

  https://link.springer.com/article/10.1007/s00439-023-02605-6

  Brain arteriovenous malformation (BAVM) is a rare but serious cerebrovascular disease whose pathogenesis has not been fully elucidated. Studies have found that epigenetic regulation, genetic variation and their signaling pathways, immune inflammation, may be the cause of BAVM the main reason. […] Studies have found that epigenetic regulation such as DNA methylation, non-coding RNAs and m6A RNA modification can regulate endothelial cell proliferation, apoptosis, migration and damage repair of vascular malformations through different target gene pathways. Gene defects such as KRAS, ACVRL1 and EPHB4 lead to a disordered vascular environment, which may promote abnormal proliferation of blood vessels through ERK, NOTCH, mTOR, Wnt and other pathways. […] Recent single-cell sequencing data revealed the diversity of various cell types within BAVM, as well as the heterogeneous expression of vascular-associated antigens, while neutrophils, macrophages and cytokines such as IL-6, IL-1, TNF-, and IL-17A in BAVM tissue were significantly increased. […] Therefore, further studies on molecular biological mechanisms will help to gain insight into the pathogenesis of BAVM and develop potential therapeutic strategies.

• #59 Genetic and epigenetic mechanisms in the development of arteriovenous malformations in the brain | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-016-0248-8

  Vascular malformations are developmental congenital abnormalities of the vascular system which may involve any segment of the vascular tree such as capillaries, veins, arteries, or lymphatics. […] The causative factor and pathogenic mechanisms of AVMs are unknown. Importantly, no marker proteins have been identified for AVM. […] Altered local hemodynamics in the blood vessels can affect cellular metabolism and may trigger epigenetic factors of the endothelial cell. […] We propose that AVMs result from a series of changes in the DNA methylation and histone modifications in the genes connected to vascular development. […] Aberrant epigenetic modifications in the genome of endothelial cells may drive the artery or vein to an aberrant phenotype. […] This review focuses on the molecular pathways of arterial and venous development and discusses the role of hemodynamic forces in the development of AVM and possible link between hemodynamic forces and epigenetic mechanisms in the pathogenesis of AVM.

• #60 Cerebral arteriovenous malformations. Part 1: cellular and molecular biology in: Neurosurgical Focus Volume 26 Issue 5 (2009) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/26/5/article-pE10.xml

  The scientific understanding of the nature of arteriovenous malformations (AVMs) in the brain is evolving. It is clear from current work that AVMs can undergo a variety of phenomena, including growth, remodeling, and/or regression and the responsible processes are both molecular and physiological. A review of these complex processes is critical to directing future therapeutic approaches. The authors performed a comprehensive review of the literature to evaluate current information regarding the genetics, pathophysiology, and behavior of AVMs. […] Understanding the complicated molecular milieu of developing AVMs is essential for defining their natural history. Growth factors, extracellular matrix proteins, and other molecular markers will be the key to unlocking novel targeted drug treatments for these brain malformations.

• #61

  https://scite.ai/reports/the-pathogenesis-of-arteriovenous-malformations-GeN5rx

  Recently, increasing attention has focused on the possible importance of venous outflow disturbance and venous hypertension in the pathogenesis and pathophysiology of AVMs. […] The potential mechanisms for this association and the implications of the present case are discussed, and the pertinent literature is reviewed. […] In such a hypothetical model, the proposed formation of the AVM parallels DAVF development: thrombosis and subsequent partial recanalization of the DVA rootlets may induce arterializations of the DVA, creating the basis for a newly formed AVM. […] Recent clinical and experimental evidence has challenged the traditional concept of the venous system as a passive element in the genesis and evolution of intracranial vascular malformations. […] Although they are traditionally thought to be congenital in origin, with an initiating event occurring in early embryologic development, some have suggested a more dynamic developmental process.

• #62 Cerebral arteriovenous malformations. Part 1: cellular and molecular biology in: Neurosurgical Focus Volume 26 Issue 5 (2009) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/26/5/article-pE10.xml

  The growth potential of AVMs and their regression may involve opposing forces supporting or inhibiting angiogenesis and vascular remodeling. A phenomenon noted in tumor angiogenesis is the need for both VEGF and ANG-2; if VEGF is absent, vessels will undergo regression if ANG-2 is present. […] The roles of the TGF family in vascular development are complex and multidimensional; for example, TGF is biphasic. In the early stages of development, TGF inhibits vascular endothelial proliferation; in later stages, it promotes the differentiation of surrounding mesenchymal cells to differentiate into pericytes and SMCs. […] The expression of VEGF is high in the endothelial layer and media of vessels in AVMs. Pathological studies have shown that almost three-quarters of AVMs resected following incomplete embolization express VEGF and Flk-1, whereas the endothelium of only one-quarter of AVMs not preoperatively embolized expresses these factors. This finding may explain why partially obliterated AVMs recur. […] The activation of this pathway signals SMC proliferation, which contributes to the vascular remodeling and growth/regression of these lesions.

• #63

  https://journals.lww.com/neur/fulltext/9900/spontaneous_obliteration_of_postoperative_residual.20.aspx

  A single draining vein has been proposed to be a common finding in patients with spontaneous obliteration of AVMs. It was noted in 86% of cases in the literature and in all the cases reported by Abdulrauf et al. that occlusion of a single vein leads to total venous outflow obstruction and stasis that leads to thrombosis and occlusion of the nidus. […] Spontaneous obliteration of postoperative residual nidus has also been recorded in two cases of a series of 700 surgically treated cases. […] Despite the rarity, angiography just prior to surgery appears to be necessary, as spontaneous obliteration may be a surprising discovery.

• #64 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8396465/

  Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. […] The lack of FDA approved medical treatments for AVMs reflects our limited understanding of the pathogenesis of AVMs, in particular how AVMs develop and progress. Mounting evidence suggests that even for familial AVMs, underlying genetic defects in the germline alone might not be sufficient for AVMs to manifest. Local events such as somatic mutations and pro-angiogenic stimuli might be additionally required drivers. […] Insights from experimental animal models employing cell-specific deletions of causative genes suggest the endothelial cell (EC) as the key cell type in AVM formation.

• #65 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://www.mdpi.com/1422-0067/22/16/9037

  Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. Therapeutic approaches are limited, and AVMs can cause significant morbidity and mortality. Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. […] The lack of FDA approved medical treatments for AVMs reflects our limited understanding of the pathogenesis of AVMs, in particular how AVMs develop and progress. Mounting evidence suggests that even for familial AVMs, underlying genetic defects in the germline alone might not be sufficient for AVMs to manifest. Local events such as somatic mutations and pro-angiogenic stimuli might be additionally required drivers.

• #66 The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

  https://www.mdpi.com/2227-9059/11/11/2876

  The treatment of symptomatic bAVMs, whether as a part of a complex inherited genetic syndrome (such as HHT), or as an isolated sporadic lesion initiated by a somatic variant within the endothelium (e.g., KRAS gain of function), represents an incredible challenge for neurosurgical teams, due to the fragility of intracranial vessels and the associated risk of stroke and hemorrhage. […] The decision for intervention is patient-specific and depends on bAVM eloquence, size, location, vascular anatomy, and complexity, as well as hemorrhage history. […] Currently no FDA-approved drug therapies exist for treating bAVM, although efforts are focused on the use of FDA-approved MEK1/2 inhibitors, as the MAPK kinase cascade (RAF-MEK-ERK) is an obligate target of KRAS in the endothelium. […] With limited treatment options for these patients, there is an urgent need to identify novel therapeutic targets based on our current understanding of bAVM pathogenesis.

• #67 The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

  https://www.mdpi.com/2227-9059/11/11/2876

  Inflammation, in particular, proves an important target for drug research based on both the “second hit” model and its overall association with intracranial hemorrhage in both bAVMs and other cerebrovascular conditions. […] Thus, we must first examine inflammation and the cell signaling networks controlling this process, and how it impacts blood–brain barrier (BBB) integrity and the neurovascular unit (NVU) in the setting of bAVM. […] Notably, BBB breakdown and vascular dysfunction (e.g., cerebral hypoperfusion) can precede cognitive decline and clinical symptoms in numerous neurological pathologies, including aging, multiple sclerosis, stroke, Alzheimer’s, and epilepsy, with the disruption of vascular function in the CNS causing ion disturbance, edema, and neuroinflammation. […] These observations have prompted researchers to investigate if either BBB dysfunction contributes to, or drives, lesion rupture in bAVM rupture as well.

• #68 Arteriovenous malformation Map2k1 mutation affects vasculogenesis | Scientific Reports

  https://www.nature.com/articles/s41598-023-35301-6

  The transcriptome changes in MAP2K1 expressing ECs provides insights into the mechanisms that contribute to AVM formation. […] Our results showing that the Map2k1 mutation in ECs affects vasculogenesis genes and pathways contributes to our understanding of AVMs pathogenesis. […] The activating MAP2K1 EC mutation may cause AVM enlargement through abnormal blood vessel production that secondarily causes overgrowth of tissues. […] Drugs that inhibit EC migration, adhesion, and angiogenesis may prove beneficial to patients with AVMs.

• #69

  https://scite.ai/reports/10.3390/ijms22169037

  Mechanistically, in addition to the TGF/BMP pathway, several other pathways, such as VEGF, mTOR, and PI3K/AKT signaling pathways, are associated with AVM formation and HHT pathogenesis. […] Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease that causes arteriovenous vascular malformations (AVMs) in different organs, including the lung. […] However, how these loss-of-function gene mutations lead to AVMs formation and what common downstream signaling they target is unknown. […] Our findings suggest that Brivanib could be an emerging new drug for HHT.

• #70 The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

  https://www.mdpi.com/2227-9059/11/11/2876

  Specifically, recent scRNA-sequencing studies suggest that compromised BBB function, inferred from loss of mature CNS endothelial BBB markers and increased expression of peripheral endothelial genes, could lead to an influx of inflammatory cells that may drive bAVM rupture. […] The recruitment of monocyte-derived cell types, as well as the activation of resident CNS cells in the brain (e.g., microglia and astrocytes), combined with a flood of secreted proteolytic enzymes and barrier-disrupting cytokines and pro-angiogenic growth factors, together with the rise in reactive oxygen species, all act to promote vascular and basement membrane breakdown. […] In this sense, blocking monocyte homing to bAVM tissue may be a possible strategy to reduce bAVM severity, although studies are needed to confirm this, including using genetic mouse models of sporadic KRAS-dependent bAVMs.

• #71 The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

  https://www.mdpi.com/2227-9059/11/11/2876

  Overall, these discoveries suggest that modulating gene expression levels and/or activity may represent a viable therapeutic strategy for preventing bAVM rupture both pre- and post-surgical intervention. […] Furthermore, they suggest that in the future a precision medicine approach to treating patients with bAVM may be possible, and indeed beneficial, to either predict or possibly prevent adverse outcomes in bAVM, such as ICH stroke.

• #72

  https://www.jci.org/articles/view/172837

  In the context of AVMs, VEGF assumes a crucial role in both development and growth. […] Elevated VEGF levels in the brains of mice with ALK1 deficiency-induced AVMs have also been linked to increased AVM-related hemorrhage rates and mortality, suggesting that VEGF is not only involved in AVM development, but also in subsequent complications. […] The majority of AVMs arise sporadically as isolated lesions. In these noninherited AVMs, the important MAPK signaling cascade plays a crucial and pathogenic role. […] In extracranial AVMs, somatic mutations in MAP2K1, encoding MEK1, have been detected in 64% of patients. […] Experimental studies utilizing mouse models have provided compelling evidence supporting the role of activated KRAS within ECs in the development of AVMs across various soft tissues, including the brain, liver, and heart. […] The unraveling of the major initiating mechanisms for AVM formation has propelled the field to think of targeted molecular therapies that could be used alone or as pre-, peri-, and postinterventional procedures.

• #73 Frontiers | Cellular loci involved in the development of brain arteriovenous malformations

  https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2022.968369/full

  Abnormal astrocytes with increased expression of glial fibrillary acidic protein (GFAP) and vimentin have been observed in human sporadic bAVMs which is associated with deregulated retinoic acid signaling. […] To date, the roles of different cellular loci in bAVM initiation and progression have not been fully studied. […] Understanding the roles of each cellular locus will help us to design targeted therapeutic strategies to treat bAVM or prevent bAVM hemorrhage.

• #74 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8396465/

  In familial AVMs, the question of why AVMs arise in seemingly random anatomic locations in an individual carrying the allele with the causative germline gene mutation within every cell has been a conundrum. A three-event hypothesis suggesting concurrence of two additional, regionally confined triggers, is mainly based on insights gained from animal studies. […] These studies suggested that a combination of a loss of one functional allele in an HHT-locus, a local loss of protein, and an angiogenic stimulus directed towards ECs might be required for AVM development in mice. […] Furthermore, determinants such as blood flow and shear stress have been identified to be contributory to AVM formation.

• #75 Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

  https://www.mdpi.com/1422-0067/22/16/9037

  A possible explanation for this phenomenon might be found in studies showing that increased flow in a microvascular bed can cause capillaries to transition to arterioles. […] The three steps of AVM development identified above were also described in patients with pulmonary AVMs (PAVMs) in HHT using high resolution CT scanning. […] In familial AVMs, the question of why AVMs arise in seemingly random anatomic locations in an individual carrying the allele with the causative germline gene mutation within every cell has been a conundrum. […] Furthermore, determinants such as blood flow and shear stress have been identified to be contributory to AVM formation. […] Further research will be required to strengthen our understanding of AVM formation, and translate these insights from animal models to humans.

• #76

  https://scholars.duke.edu/individual/pub1646147

  Pediatric arteriovenous malformations (AVMs) are rare but carry a risk of devastating neurological morbidity and mortality. […] The complex etiology of pediatric AVMs persists as an impediment to a comprehensive understanding of pathogenesis and subsequent targeted gene therapies. […] The Ephrin B2/EphB4 (RASA-1, KRAS, and MEK) signaling axis, hemorrhagic telangiectasia, NOTCH, and TIE2 receptor complexes (PIK3CA and mTOR), in addition to other isolated gene variants, have been implicated in AVM pathogenesis. […] Furthering the understanding of the molecular mechanisms of AVM pathogenesis will lead to future novel therapies and treatment paradigms.

• #77 Frontiers | Cellular loci involved in the development of brain arteriovenous malformations

  https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2022.968369/full

  Abnormal astrocytes with increased expression of glial fibrillary acidic protein (GFAP) and vimentin have been observed in human sporadic bAVMs which is associated with deregulated retinoic acid signaling. […] To date, the roles of different cellular loci in bAVM initiation and progression have not been fully studied. […] Understanding the roles of each cellular locus will help us to design targeted therapeutic strategies to treat bAVM or prevent bAVM hemorrhage.

Zobacz więcej