An Updated Review on the Pathogenesis of Brain Arteriovenous Malformations and Its Therapeutic Targets

Abstract

Brain arteriovenous malformations (bAVMs) are associated with a high risk of intracerebral hemorrhage, which causes severe complications in patients. Although the genetic factors leading to hereditary bAVMs have been extensively investigated, their pathogenesis are still under study. This review examines updated data on the molecular and genetic aspects of bAVMs, the architecture of microvasculature, the roles of angiogenic factors, and signaling pathways. The compiled information may help us understand the pathogenesis of both sporadic and hereditary bAVMs and develop appropriate preemptive treatment approaches.

Introduction

Brain arteriovenous malformations (bAVMs) often present asymptomatically but may also cause headaches, seizures, and intracerebral hemorrhage (ICH). The rupture of an AVM can be fatal. The current treatment methods include surgical resection, endovascular embolization, and stereotactic radiosurgery, aiming particularly to reduce the risk of ICH.

Traditionally considered congenital, bAVMs are now understood as dynamic lesions rather than static entities.^1,2) The description of de novo bAVM formation indicates that multiple factors contribute to their pathogenesis. AVM tissue is considered to be a dynamic, biologically active angiogenic and inflammatory lesion, not a static, congenital lesion.

Two proposed mechanisms for the formation of bAVMs are as follows³⁾: (1) Abnormal sprouting angiogenesis leads to anomalous direct connections between arteries and veins, and (2) progressive dilation of existing capillary beds results in high-flow shunting from arterial to venous circulation. While these mechanisms appear specific to rodent models,⁴⁾ the pathogenesis of bAVMs in humans remains uncertain.

Previous research indicates that both genetic and environmental factors play a role in the development and progression of bAVMs. Some bAVM cases are linked to familial vascular malformation syndromes due to germline or inherited mutations, which includes hereditary hemorrhagic telangiectasia (HHT) and capillary malformation (CM)-AVM, resulting from germline mutations in genes like ENG, ALK1, SMAD4, and RASA1.^5,6) These genes had important roles in angiogenesis and vascular remodeling. Among the general population, sporadic AVMs represent most (>95%) of the disease burden, with little understanding of the associated causes. Several studies have investigated susceptibility genes and variants to elucidate the hereditary mechanisms of bAVMs.

This review encompasses the formation of bAVMs, the roles of inflammatory and angiogenic factors, signaling pathways, and pharmacological therapeutic targets.

Vascular Development

The normal vascular system develops through two distinct processes: vasculogenesis (de novo vessel formation during embryogenesis) and angiogenesis (the expansion of a pre-existing vascular network through sprouting or splitting of vessels).^7,8) Subsequent growth of the vertebrate vasculature occurs entirely by angiogenesis. This process begins with vascular EC proliferation and migration. The second process involves vascular stabilization, where ECs form capillary tubes, strengthen their intercellular junctions, and recruit SMCs to their walls.⁷⁾

Vasculogenesis

Vasculogenesis primarily occurs during embryogenesis, but it can also happen in adults under certain pathological conditions such as ischemia or tumor growth. It involves creating a primitive vascular network through the differentiation of endothelial precursor cells (EPCs) or angioblasts into ECs. Under the influence of VEGF and VEGF receptor-2 (VEGFR-2) signaling pathways, EPCs and hematopoietic stem cells aggregate in blood islands, leading to the formation of a primitive vascular network.

Angiogenesis

Angiogenesis is the process of forming new blood vessels from pre-existing ones. There are two main types: sprouting angiogenesis and intussusceptive angiogenesis. VEGF-A, a member of the VEGF family, plays a crucial role in blood vessel formation and growth. In sprouting angiogenesis, new vessels branch off from existing ones. Degradative enzymes, such as matrix metalloproteinases (MMPs), initiate the proteolysis of the basement membrane, which then mobilizes ECs and pericytes.^9,10) Proteinase activity triggers the release of angiogenic factors (such as VEGF and FGF) and anti-angiogenic molecules (such as endostatin and platelet factor-4), completing the process of angiogenesis.¹¹⁾

While the pathogenesis of bAVMs is not fully understood, both human and animal studies suggest a role in the dysregulation of angiogenesis. For instance, human bAVM ECs exhibit aberrant angiogenic characteristics, such as upregulated VEGF pathway genes and increased EC turnover.

Brain AVMs form at the interface between arterial and venous endothelia, where the capillary endothelium normally resides. Vascular malformations severely disrupt the angiogenic process, which involves ECs forming capillary tubes, strengthening intercellular junctions, and recruiting SMCs to the vessel wall.¹²⁾ The constitution of bAVMs consists of aberrant vessels that are not fully differentiated and inadequately matured, histopathologically lacking a true capillary bed.¹³⁾

Microvasculature

Cerebral blood vessels consist of endothelial cells (ECs), vascular smooth muscle cells (SMCs), and pericytes. Recent research on bAVMs has predominantly focused on the endothelium. ECs, which play a central role in the microvasculature forming the blood-brain barrier (BBB), create a single-cell layer lining the vascular lumen and serve as a crucial interface within the BBB. While BBB disruption is documented in bAVMs,¹⁴⁾ unruptured bAVMs often exhibit microhemorrhages, potentially serving as predictors of future rupture.¹⁵⁾ However, the precise impact of vascular EC and SMC functions on the phenotypic manifestation of bAVMs remains uncertain.

ECs

The behavior of ECs during vascular development is governed by crucial growth factor families, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiopoietin, and the transforming growth factor-beta (TGF-β)/bone morphogenetic protein (BMP) families. An essential pathway for EC-vascular SMC and pericyte interaction involves the platelet-derived growth factor-B (PDGFB)/PDGF receptor-β pathway.

In the context of bAVMs, ECs exhibit an immature and hyperactive phenotype, characterized by elevated expression levels of pro-angiogenic factors. This phenomenon leads to varying degrees of BBB disruption, resulting in microhemorrhages and, in severe cases, rupture. VEGF plays a pivotal role in promoting the angiogenic phenotype through RAS activation.¹⁶⁾ Additionally, there is evidence suggesting that KRAS-activating mutations in ECs may contribute to the pathological features of bAVMs via the RAS-mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) pathway.

ECs from bAVMs proliferate and migrate more rapidly, forming abnormal vascular tubules in vitro.¹⁷⁾ Experimental animal models replicate certain features observed in human bAVMs, including dilated vessels, arteriovenous shunts, high-flow lesions, and nidus formation.^18,19) The combination of EC-specific ALK1 deletion and VEGF administration in the brain induced a lesion in a mouse model, similar to a human AVM.²⁰⁾ Additionally, adenovirus-mediated EC-selective ALK1 deletion and VEGF overexpression also generate lesions resembling human bAVMs,⁴⁾ suggesting that alterations in EC function and angiogenesis play a role in bAVM pathogenesis. Furthermore, the endothelium in bAVMs exhibits a pro-inflammatory phenotype, with upregulated endothelial adhesion molecules and cytokines contributing to BBB breakdown and the infiltration of circulating inflammatory cells.²¹⁾

SMCs

Vascular SMCs constitute the primary cellular components of vessel walls in both arteries and veins. It has been proposed that SMCs are diminished in bAVMs.²²⁾ In vitro, SMCs derived from bAVMs form elongated tubes, and their migration and proliferation surpass those of normal brain vascular SMCs.²³⁾

Pericytes

Pericytes, situated within the vascular basement membrane shared with adjacent ECs, play critical roles in capillary walls. In both human bAVMs and rodent models, pericytes are reduced,^14,24) particularly in ruptured human AVMs.¹⁴⁾ This reduction in perivascular cell coverage is associated with increased vessel permeability and a higher risk of bleeding.²⁵⁾ During bAVM angiogenesis, the recruitment of mural cells is diminished.²⁶⁾ The extent of pericyte loss correlates with the severity of BBB disruption and microhemorrhage in unruptured AVMs.¹⁴⁾ Pericytes are essential for angiogenesis and maintaining vessel stability, engaging in crosstalk with angiopoietin signaling. Notably, angiopoietin-2 is overexpressed in bAVMs compared to controls.^27,28) Additionally, Sun et al. discovered that KRASG12V expression in ECs reduces pericyte recruitment and disrupts vascular basement membrane formation.²⁵⁾ The abnormal vessels observed in bAVMs partly result from downstream defects in pericyte behavior and their signaling mechanisms.

Molecular Signatures of bAVM

Pro-inflammatory mediators

Previous literature has established a link between inflammatory factors and bAVM pathogenesis and rupture. AVMs are lesions that can grow or contract at the cellular level in response to inflammatory cytokines and angiogenic factors and their receptors on ECs.²⁹⁾ Inflammation stimulates lymphocytes to produce cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-α), which increase the production of VEGF. These cytokines activate nuclear factor-kappa B , binding to the VEGF and IL-8 gene promoter regions, upregulating them and promoting AVM angiogenesis.³⁰⁾ The genes for the main proinflammatory cytokines contain many single nucleotide polymorphisms (SNPs) that cause varying degrees of inflammatory reactions and modify the degree of vascular dysmorphogenesis. The MMPs families are downstream inflammatory mediators involved in bAVM. The levels of MMP-9 protein and the activity of MMP-9 and MMP-2 were increased in unruptured bAVMs.³¹⁾ IL-6, a pro-inflammatory cytokine, correlates with activated MMP-9 levels; thus, the hypothesis that IL-6 may be a potential marker for hemorrhage risk emerged.³¹⁾ IL-6 polymorphisms might regulate inflammatory signaling and activate ECs to promote the progression of bAVMs.³²⁾

A recent study revealed an association between an SNP in the TNF-α gene and an increased likelihood of developing a new ICH.³³⁾ The TNF-α and apolipoprotein E genotypes may contribute to shared phenotypes related to heightened vascular instability, potentially increasing the risk of hemorrhagic outcomes even after treatment, which can result from various distinct mechanisms. Additionally, inflammatory cells – including macrophages and neutrophils – have been detected in surgical specimens of human bAVMs.³⁴⁾

Growth factors signaling pathway

VEGF is expressed at high levels in bAVM ECs, particularly in ruptured bAVMs.³²⁾ This factor encodes a heparin-binding protein and induces the proliferation and migration of vascular ECs.³⁵⁾ VEGF and the corresponding endothelial receptor tyrosine kinases are the major regulators of vasculogenesis and angiogenesis. The disruption of VEGF signaling is involved in the formation and progression of bAVMs.

Increased expression of VEGF in the endothelium and other cells of surgical specimens from bAVMs implies that VEGF is involved in EC proliferation and angiogenesis in bAVMs.^28,36) VEGF and angiopoietin-2 protein were abundantly expressed in human bAVM lesions compared to the normal cerebral cortex.³⁷⁾ Furthermore, the nidus size is larger in lesions positive for VEGF-A or VEGFR-A receptor staining. VEGF-mediated angiogenesis plays a pathogenic role in lesion enlargement.³⁶⁾ Extrapolating from animal models, VEGF may contribute to the hemorrhagic tendency of bAVMs.³⁸⁾ The inhibition of VEGF signaling prevented bAVM formation in experimental animal models.³²⁾ VEGF overexpression increases the permeability of the BBB and is considered a risk factor for hemorrhage.³⁹⁾

TGF-β signaling pathway

TGF-β is a multifunctional cytokine that impacts brain vascular development and is implicated in both bAVMs and cavernous malformations.⁴⁰⁾ In humans, SNPs in ALK1, ENG, or SMAD9 may be associated with an increased risk of sporadic AVMs.⁴¹⁾ However, the role of TGF-β signaling in the formation of non-HHT, sporadic bAVMs remains to be defined.

The BMPs are members of the TGF-β superfamily, and their signaling plays a critical role in modulating sprouting angiogenesis. The BMP and Notch signaling pathways are essential for vascular development and homeostasis. A lack of BMP inhibition induces the expression of Notch components in ECs, resulting in bAVMs.⁴²⁾

Notch

The Notch pathway serves as a critical mediator in the differentiation of arteries and veins.⁴³⁾ An AVM arises due to impaired arterial or venous differentiation during early angiogenesis. Deregulated arterial specification signaling might play a significant role in the pathogenesis of AVMs.⁴⁴⁾ Recently, Notch signaling was shown to be involved in the formation of non-syndromic, sporadic bAVMs.³⁰⁾ Notch1 was overexpressed in ruptured AVMs,⁴⁵⁾ and polymorphisms of the Notch4 gene have also been associated with human AVM formation and hemorrhage.⁴⁶⁾

RAS-MAPK-ERK signaling pathway

KRAS, a member of the RAS family, controls multiple signaling pathways that affect various cellular processes. (Fig. 1) RAS proteins are mainly regulated by VEGF, and RAS regulates VEGF expression and angiogenesis through downstream RAS-MAPK activities. KRAS activation influences cellular microenvironmental homeostasis such as cell proliferation, migration, and angiogenesis. Most high-flow vascular malformations, including bAVMs, have mutations mainly in the RAS-MAPK-ERK pathway, which are common in cancer.⁴⁷⁾ Some sporadic bAVMs and extra-neural AVMs have somatic mutations in genes of the RAS-MAPK pathway.⁴⁷⁾ Endothelial-specific KRAS p.G12V and p.G12D caused bAVM in mice and embryonic zebrafish.⁴⁸⁾ These findings in bAVM specimens also supported the two-hit hypothesis that environmental factors might damage DNA in ECs, leading to abnormal vascular construct formation in a way similar to tumorigenesis and rupture in bAVM.⁴⁹⁾ Several studies have shown that activating mutations in the MAPK signaling pathway are significantly linked to vascular malformations.^47,50) The mutations p.G12V and p.G12D in KRAS were activated in more than half of bAVM tissue samples.⁵¹⁾ In sporadic bAVMs, KRAS G12V or G12D mutations,⁵²⁾ p.G12C,⁵³⁾ and p.G12A⁵⁰⁾ have been reported. Mutation variant frequencies had a negative correlation with nidus volumes and largest diameters, but not with age.⁵⁰⁾ Histologic characteristics were evenly distributed between KRAS-mutant and non-mutant groups.⁵³⁾ KRAS mutations in human bAVM increased ERK activity that was reversed by inhibition of MAPK–ERK signaling.⁴⁷⁾

Fig. 1. Signal transduction pathways in endothelial cells and the main genetic mutations associated with vascular malformations. The key signaling pathways, PI3K/AKT/mTOR and RAS/RAF/MEK/ERK, Notch, TGF-β, and TNF-α, control cellular growth, apoptosis, and differentiation through complex transcriptional regulation. Potential treatments are indicated in a square. ERK: extracellular signal-regulated kinase; MEK: MAPK/ERK kinase; mTOR: mammalian Target of Rapamycin; PI3K: phosphoinositide 3-kinase; PTEN: phosphatase and tensin homolog; TGF-β: transforming growth factor-beta; TNF-α: tumor necrosis factor-alpha; VEGF: vascular endothelial growth factor.

The RAF-MAPK/ERK kinase (MEK)-ERK pathway is a classic downstream target of KRAS signaling. Mosaic-activating variants in the genes KRAS, NRAS, BRAF, and MAP2K1 of the RAS/MAPK pathway were found in children with spontaneous intracranial and extracranial vascular malformation lesions.⁵²⁾ Phenotypic heterogeneity in bAVM stems from timing, mutation differences, tissue or cell type, as well as through inter-crosstalks with other pathways. The cells with mutated KRAS can be a therapeutic target in the treatment of bAVM.⁵⁴⁾ On the other hand, there are opposing views that this may suggest that the histology of bAVMs is a reflection of MAPK–ERK activation in general, regardless of the initiating event.^51,53) The underlying mechanism by which KRAS mutations affect the clinical presentation or natural history of bAVM remains unclear. However, one study reported that KRAS variant allele frequency is negatively correlated with the lesion size.⁵⁵⁾

PI3K-AKT pathway

The phosphoinositide 3-kinase (PI3K)-AKT pathway is another downstream signaling pathway activated by KRAS. Venous and lymphatic are low-flow vascular malformations, mainly associated with PI3K-AKT-mammalian Target of Rapamycin (mTOR).⁵⁶⁾ The mutations in this pathway are commonly linked to cancer, and regulate the proliferation, migration, and survival of ECs. This pathway is a critical regulator of the angiogenic process. Somatic mutations have been observed in bAVMs in the PI3K pathway. The PI3K-AKT-mTOR pathway is a potential therapeutic target for bAVMs. However, somatic mutations in the PI3K pathway in high-flow AVMs have not been identified yet.

Non-coding RNAs

Non-coding RNAs are key to future minimally/non-invasive diagnostic and therapeutic strategies in bAVM patients.⁵⁷⁾ Most non-coding RNA-based studies in bAVMs preferentially target miRNAs that are associated with angiogenesis. MiR-137 and miR-195 modify the phenotypic characteristics of AVM SMCs to act as vasculogenic suppressors in AVMs.²³⁾ A 3-fold reduction in miR-18a levels was observed in ECs isolated from the bAVM nidus.¹⁷⁾ MiR-18a inhibits several important angiogenesis pathways, such as VEGF, Notch, MMP, and BMP-4/ALK signaling, which are aberrantly overexpressed in AVM pathogenesis.

Genetic Signatures of bAVM

Genetic variants linked to bAVM rupture have been detected in many reports. We can understand the genetics and pathogenesis of bAVMs through the detection of gene mutations and genetic risk factors related to bAVMs. The genetic hypothesis for the formation of AVMs proposes a “two-hit” mechanism, wherein a hereditary mutation in one copy of a cerebrovascular malformation gene is followed by a somatic mutation in the other copy.⁷⁾ The second “hit” could be environmental, implying an interaction between hemodynamic and genetic factors in vasculogenesis.

Hereditary AVM

HHT

HHT, also known as Osler-Weber-Rendu syndrome, is a rare autosomal dominantly inherited vascular disease characterized by mucocutaneous telangiectasia and AVMs in multiple organs, including the brain.⁵⁸⁾ The prevalence of HHT is estimated at 1 in 5000–8000 people. The disease is classified into the types based on germline mutations caused by heterozygous loss-of-function mutations in ENG (type 1), ACVRL1 (type 2), or SMAD4.⁵⁹⁾ Types 1 and 2 account for >90% of patients with HHT.⁶⁰⁾ Mutations in SMAD4 cause a combined syndrome of juvenile polyposis and HHT, accounting for 2% of HHT cases.⁶¹⁾ All three genes mutated in HHT are part of a common signaling pathway encoding for TGF-β and BMP growth factors.⁵⁹⁾ Recently, BMP9 and BMP10 have been identified as high-affinity activators of ALK1, relevant for HHT pathogenesis.^60,62)

Approximately 5%–20% of HHT cases have at least one bAVM,⁶³⁾ and the presence of multiple bAVMs is highly predictive of the HHT diagnosis.⁶⁴⁾ Brain vascular malformations are pial arteriovenous fistula, nidus type AVM, or capillary vascular malformation without shunting.⁶⁵⁾ BAVMs are highly observed in HHT1 (13.4%) compared to HHT2 (2.4%).^66,67) The majority of lesions are smaller than sporadic bAVMs. No significant differences in age at first bAVM diagnosis, prevalence of ICH history, age at ICH, or other manifestations of bAVMs were observed among different genes involved in HHT.⁶⁸⁾

According to a two-hit mechanism hypothesis for AVM pathogenesis in HHT, both genetic mutations in ENG or ACVRL1 and physiological or environmental factors are essential for bAVM development. The second hit may be another genetic mutation such as somatic mutation.⁶⁹⁾ Recent research implied that the development of vascular malformations in HHT may depend on the biallelic loss of ENG or ACVRL1. By manipulating ENG and ACVRL1, genetic mouse models of HHT were generated. Homozygous knockout mice did not survive embryogenesis. In adult mice with homozygous deletions of ACVRL1 or ENG, brain AVMs were induced by additional stimulation with VEGF. This showed that lesion development requires both genetic mutation and angiogenic stimulation.^4,20)

CM-AVM

A form of RASopathy syndromes, CM-AVM, is another genetic syndrome linked to bAVMs.⁶⁾ Cutaneous CMs of the brain, spine, and soft tissues, as well as high-flow intracranial AVMs or AVFs, are features of this autosomal dominant disorder. CM-AVM1 is related to a heterozygous pathogenic variant of RASA1 in more than 50% of patients, while CM-AVM2 is due to mutations in EphB4, the direct upstream effector of RASA1.⁷⁰⁾ RASA1 produces the p120 Ras-GTPase activating protein (p120-RasGAP), which restricts RAS signaling. Increased RAS-MAPK pathway signaling is caused by inactivating mutations in RASA1. EPHB4 also stimulates p120-RasGAP, having similar downstream effects on the MEK/ERK pathway as RASA1. BAVMs occurred more often in patients with CM-AVM1 (10%) than in those with CM-AVM2 (3%). The phenotypic resemblance between CM-AVM1 and CM-AVM2 indicates that RASA1 and EPHB4 have overlapping functions in vascular development and embryogenesis.⁷¹⁾

Epigenetic mechanisms in AVM formation

The epigenetic landscape is also crucial for understanding the development and growth of bAVM.⁷²⁾ Some researchers tried to clarify these epigenetic signal. DNA methylation and changes in histone modifications during vascular development have also been documented. The current literature on genetic mechanisms involved in bAVM formation and their influence on signaling pathways offers a wide range of possibilities for future therapeutic options.

Future Therapeutic Targets

A non-invasive, prompt, and cell-specific therapy for AVM would be ideal. Pharmacological treatments aim to inhibit angiogenesis and inflammation in AVM signaling. Molecular pathways disrupted in bAVMs, such as TGF-β, Notch, and VEGF have been a target for bAVM treatment. Studies using mouse models and human AVM specimens have highlighted the role of VEGF as a key mediator of AVM formation and progression.⁷³⁾ Bevacizumab, a humanized VEGF monoclonal antibody, directly targets VEGF. Intravenous bevacizumab was effective in reducing gastrointestinal bleeding and epistaxis in patients with HHT, according to a report.⁷⁴⁾ The use of bevacizumab to neutralize VEGF overexpression prevented cutaneous AVM formation in ALK1-deficient mice and normalized arteriovenous shunting.⁷⁵⁾ Uysal et al. reported a case of perilesional edema of an AVM after SRS that showed brain edema reduction.⁷⁶⁾ However, anti-VEGF treatments have significant side effects, such as a higher risk of hemorrhage.⁷⁷⁾

An angiotensin II receptor antagonist for hypertension treatment, losartan, reduced vascular dysplasia and arteriovenous shunting in a zebrafish model of bAVMs induced by knockdown of the TGF-β receptor ALK1.⁷⁸⁾ Thalidomide treatment in HHT increased endothelial PDGFB expression, which resulted in the recruitment of mural cells and vessel stabilization.⁷⁹⁾ Targeted drug therapy based on the most frequent KRAS somatic mutations in bAVM might be a feasible solution. Mutations affecting the RAS/BRAF/MEK/ERK pathway (e.g., capillary malformation, CM-AVM, bAVM, and spinal AVM) could potentially be targeted by BRAF inhibitors (e.g., vemurafenib) and/or MEK inhibitors (e.g., trametinib and cobimetinib).^50,71,80) Recent studies have shown that MEK inhibitors can suppress angiogenesis and Notch pathway activation in KRASG12V ECs.²⁵⁾

A MEK/ERK inhibitor, trametinib, reduces KRASG12V-induced bAVM growth in mice.⁴⁸⁾ Trametinib treatment showed efficacy in limited cases of AVM patients with decreased lesion size and symptoms.⁵²⁾ A genotype-guided approach was used for an AVM over the left scapular region in a child. In-frame deletion of MAP2K1 was found in a specimen of the AVM and saliva. Trametinib treatment caused a significant reduction in overall volume after 6 months.⁸¹⁾ Targeting the KRAS-MAPK pathway has potential for bAVM treatment, but more studies are needed to assess tolerability, adverse effects, and optimal treatment parameters.

The PI3K-AKT-mTOR pathway is a promising target for treatment. Sirolimus inhibits angiogenesis by downregulating the PI3K/AKT signaling pathway and the expression of VEGF in animal models.⁸²⁾ In one study, all extracranial AVM patients responded favorably to the combination of sirolimus therapy followed by endovascular embolization, and two-thirds of the patients showed a near-complete response.⁸³⁾ In a pediatric patient with multiple AVMs, a 6-month trial of oral sirolimus resulted in fewer symptoms. Downstream signaling of this pathway is vital for promoting angiogenesis in AVMs.

Thalidomide or lenalidomide treatment reduced the number of dysplastic vessels and hemorrhage and increased mural cell (vascular SMCs and pericytes) coverage in bAVM lesions.²²⁾ However, thalidomide has its own risks, such as ischemic stroke, ischemic cardiomyopathy, and catastrophic epistaxis, each previously reported in trials testing thalidomide for HHT treatment.⁷⁷⁾ The focused inhibition of pro-angiogenic pathways, including VEGF, has also garnered interest for potential therapeutic advancement in treating bAVMs. VEGF neutralization can prevent and normalize AVMs in an animal model of HHT2, an autosomal-dominant disorder characterized by telangiectasia and AVMs in multiple organs.⁷⁵⁾

Inflammatory cells and their processes are linked to both ruptured and unruptured bAVMs. Researchers are investigating the possible impact of anti-inflammatory drugs such as minocycline, an MMP-9 inhibitor, and pyrrolidine dithiocarbamate in bAVM treatment. In a mouse bAVM model, treatment with minocycline attenuated cerebral MMP-9 activity, whereas pyrrolidine dithiocarbamate suppressed approximately 80% of the cerebral MMP-9 activity.³⁸⁾ Both drugs also reduced the occurrence of VEGF-induced ICH strokes. While anti-inflammatory drugs have not yet substantially influenced the established clinical care standards for most bAVM patients, findings from mouse models and recent discoveries highlighting inflammation’s role in bAVM development and rupture indicate that therapies aimed at this process could be an effective approach to mitigate bAVM severity and enhance patient outcomes.

Conclusions

The pathogenesis of bAVMs remains incompletely understood, and investigations into genetic mutations associated with bAVMs are crucial for understanding their pathogenesis and identifying potential therapeutic targets. Insights from various research perspectives, including molecular and genetic signatures, signaling pathways, and microvasculature, could enhance our understanding of bAVM development and pave the way for innovative therapeutic strategies in the near future.

Disclosure Statement

The author declares that he has no conflicts of interest.