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Biomedicines
Special Issues
Vascular Malformation: From Pathophysiology, Clinical Manifestations to Novel Therapeutic Approaches
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Vascular Malformation: From Pathophysiology, Clinical Manifestations to Novel Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: 31 January 2025 | Viewed by 10629

Special Issue Editors

Dr. Hua Su

E-Mail Website
Guest Editor
Center for Cerebrovascular Research, University of California, San Francisco, CA, USA
Interests: brain arteriovenous malformation; angiogenesis; stroke; neuroinflammation; vascular integrity; gene therapy
Dr. Li Ma

E-Mail Website
Guest Editor
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
Interests: cerebrovascular malformation; stroke; neurosurgery

Special Issue Information

Dear Colleagues,

Arteriovenous malformations (AVMs) are active angiogenic lesions consisting of tangles of abnormal vessels shunting blood directly from arteries to veins without a true capillary bed. Patients with AVMs are at risk of a hemorrhage in their internal organs. The hemorrhage from brain AVM (bAVM) can cause life-threatening intracranial hemorrhage. The mechanism of AVM formation is not fully understood. More than 95% bAVM cases are sporadic and do not have a family history. The causative gene for sporadic bAVM is unknown. Recent studies identified somatic mutations in genes in RAS-MAPK pathway in sporadic bAVMs and peripheral AVMs. However, the significance of these genes in AVM development needs to be studied further. About 5% bAVM cases are familial. The existing treatment modalities for AVM have considerable adverse effects. With the advance of imaging techniques, more asymptomatic AVM patients will be diagnosed. The treatment of asymptomatic patients has become increasingly controversial because the natural history of these patients may be less morbid than invasive therapy. Therefore, uncovering AVM pathogenesis and identifying targets for the development of specific medical therapies are urgently needed. This Special Issue focuses on the research topic of molecular mechanisms underlying AVM development and progression, clinical management, and targets for the development of new therapies. We welcome both original research and review manuscripts.

Dr. Hua Su
Dr. Li Ma
Guest Editors

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Keywords

  • arteriovenous malformation
  • vascular malformation
  • hereditary hemorrhagic telangiectasia
  • KRAS
  • activin receptor-lime kinase 1
  • endoglin
  • angiogenesis
  • anti-angiogenesis
  • animal models

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Published Papers (6 papers)

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Research

Jump to: Review

11 pages, 4198 KiB  
Article
Increasing Endoglin Deletion in Endothelial Cells Exacerbates the Severity of Brain Arteriovenous Malformation in Mouse
by Zahra Shabani, Leandro Barbosa Do Prado, Rui Zhang, Wan Zhu, Sonali S. Shaligram, Alka Yadav, Calvin Wang and Hua Su
Biomedicines 2024, 12(8), 1691; https://doi.org/10.3390/biomedicines12081691 - 30 Jul 2024
Viewed by 2296
Abstract
Endoglin (ENG) mutation causes type 1 hereditary hemorrhagic telangiectasia (HHT1). HHT1 patients have arteriovenous malformations (AVMs) in multiple organs, including the brain. In mice, Eng deletion induced by R26RCreER or SM22αCre leads to AVM development in the brain and other organs. [...] Read more.
Endoglin (ENG) mutation causes type 1 hereditary hemorrhagic telangiectasia (HHT1). HHT1 patients have arteriovenous malformations (AVMs) in multiple organs, including the brain. In mice, Eng deletion induced by R26RCreER or SM22αCre leads to AVM development in the brain and other organs. We hypothesized that an increase in Eng- negative ECs will enhance AVM severity. To increase EC Eng deletion, we used a codon-improved cre (icre), which is more potent in recombination of the floxed alleles than the wild-type (WT) cre. R26RCreER;Engf/f mice that have a Rosa promoter driving and tamoxifen (TM)-inducible WT cre expression globally, and PdgfbiCreER;Engf/f mice that have a Pdgfb promoter driving and TM-inducible icre expression in ECs were treated with three intra-peritoneal injections of TM (2.5 mg/25 g of body weight) to delete Eng globally or in the ECs. AAV-VEGF was stereotactically injected into the brain to induce brain focal angiogenesis and brain AVM. We found that icre caused more Eng deletion in the brain, indicated by a lower level of Eng proteins (p < 0.001) and fewer Eng-positive ECs (p = 0.01) than mice with WT cre. Mice with icre-mediated Eng deletion have more abnormal vessels (p = 0.02), CD68+ macrophages (p = 0.002), and hemorrhage (p = 0.04) and less vascular pericyte and smooth muscle coverage than mice with WT cre. In addition, arteriovenous shunts were detected in the intestines of icre mice, a phenotype that has not been detected in WT cre mice before. RNA-seq analysis showed that 8 out of the 10 top upregulated pathways identified by gene ontology (GO) analysis are related to inflammation. Therefore, the increase in Eng deletion in ECs exacerbates AVM severity, which is associated with enhanced inflammation. Strategies that can reduce Eng-negative ECs could be used to develop new therapies to reduce AVM severity for HHT1 patients. Full article
(This article belongs to the Special Issue Vascular Malformation: From Pathophysiology, Clinical Manifestations to Novel Therapeutic Approaches)
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14 pages, 6581 KiB  
Article
VEGFR2 Expression Correlates with Postnatal Development of Brain Arteriovenous Malformations in a Mouse Model of Type I Hereditary Hemorrhagic Telangiectasia
by Chul Han, Candice L. Nguyen, Lea Scherschinski, Tyler D. Schriber, Helen M. Arthur, Michael T. Lawton and Suk Paul Oh
Biomedicines 2023, 11(12), 3153; https://doi.org/10.3390/biomedicines11123153 - 27 Nov 2023
Cited by 1 | Viewed by 1251
Abstract
Brain arteriovenous malformations (BAVMs) are a critical concern in hereditary hemorrhagic telangiectasia (HHT) patients, carrying the risk of life-threatening intracranial hemorrhage. While traditionally seen as congenital, the debate continues due to documented de novo cases. Our primary goal was to identify the precise [...] Read more.
Brain arteriovenous malformations (BAVMs) are a critical concern in hereditary hemorrhagic telangiectasia (HHT) patients, carrying the risk of life-threatening intracranial hemorrhage. While traditionally seen as congenital, the debate continues due to documented de novo cases. Our primary goal was to identify the precise postnatal window in which deletion of the HHT gene Endoglin (Eng) triggers BAVM development. We employed SclCreER(+);Eng2f/2f mice, enabling timed Eng gene deletion in endothelial cells via tamoxifen. Tamoxifen was given during four postnatal periods: P1–3, P8–10, P15–17, and P22–24. BAVM development was assessed at 2–3 months using latex dye perfusion. We examined the angiogenic activity by assessing vascular endothelial growth factor receptor 2 (VEGFR2) expression via Western blotting and Flk1-LacZ reporter mice. Longitudinal magnetic resonance angiography (MRA) was conducted up to 9 months. BAVMs emerged in 88% (P1–3), 86% (P8–10), and 55% (P15–17) of cases, with varying localization. Notably, the P22–24 group did not develop BAVMs but exhibited skin AVMs. VEGFR2 expression peaked in the initial 2 postnatal weeks, coinciding with BAVM onset. These findings support the “second hit” theory, highlighting the role of early postnatal angiogenesis in initiating BAVM development in HHT type I mice. Full article
(This article belongs to the Special Issue Vascular Malformation: From Pathophysiology, Clinical Manifestations to Novel Therapeutic Approaches)
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Review

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16 pages, 308 KiB  
Review
Considerations for the Use of Stereotactic Radiosurgery to Treat Large Arteriovenous Malformations
by Jong Hyun Lim and Myung Ji Kim
Biomedicines 2024, 12(9), 2003; https://doi.org/10.3390/biomedicines12092003 - 3 Sep 2024
Viewed by 662
Abstract
Stereotactic radiosurgery (SRS) is an effective treatment strategy for cerebral arteriovenous malformations (AVMs). Aggressive treatment achieving complete obliteration is necessary to prevent further intracranial hemorrhage and neurological deficits. However, SRS treatment of large AVMs (>10 cm3) is challenging. To prevent toxicity [...] Read more.
Stereotactic radiosurgery (SRS) is an effective treatment strategy for cerebral arteriovenous malformations (AVMs). Aggressive treatment achieving complete obliteration is necessary to prevent further intracranial hemorrhage and neurological deficits. However, SRS treatment of large AVMs (>10 cm3) is challenging. To prevent toxicity in the normal brain tissue, it is imperative to reduce the radiation dose as the lesion volume increases; however, this also reduces the rate of obliteration. In this study, we review the various radiosurgical approaches for treating large AVMs and their outcomes, and suggest ways to improve treatment outcomes during SRS for large AVMs. Full article
(This article belongs to the Special Issue Vascular Malformation: From Pathophysiology, Clinical Manifestations to Novel Therapeutic Approaches)
41 pages, 2163 KiB  
Review
Pathophysiology in Brain Arteriovenous Malformations: Focus on Endothelial Dysfunctions and Endothelial-to-Mesenchymal Transition
by Jae Yeong Jeong, Adrian E. Bafor, Bridger H. Freeman, Peng R. Chen, Eun S. Park and Eunhee Kim
Biomedicines 2024, 12(8), 1795; https://doi.org/10.3390/biomedicines12081795 - 7 Aug 2024
Viewed by 1197
Abstract
Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or [...] Read more.
Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to understand the detailed cellular and molecular mechanisms involved, which will enable the development of safer and more effective treatment options. Endothelial cells (ECs), the cells that line the vascular lumen, are integral to the pathogenesis of bAVMs. Understanding the fundamental role of ECs in pathological conditions is crucial to unraveling bAVM pathophysiology. This review focuses on the current knowledge of bAVM-relevant signaling pathways and dysfunctions in ECs, particularly the endothelial-to-mesenchymal transition (EndMT). Full article
(This article belongs to the Special Issue Vascular Malformation: From Pathophysiology, Clinical Manifestations to Novel Therapeutic Approaches)
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18 pages, 963 KiB  
Review
Defining the Role of Oral Pathway Inhibitors as Targeted Therapeutics in Arteriovenous Malformation Care
by Ann Mansur and Ivan Radovanovic
Biomedicines 2024, 12(6), 1289; https://doi.org/10.3390/biomedicines12061289 - 11 Jun 2024
Viewed by 1132
Abstract
Arteriovenous malformations (AVMs) are vascular malformations that are prone to rupturing and can cause significant morbidity and mortality in relatively young patients. Conventional treatment options such as surgery and endovascular therapy often are insufficient for cure. There is a growing body of knowledge [...] Read more.
Arteriovenous malformations (AVMs) are vascular malformations that are prone to rupturing and can cause significant morbidity and mortality in relatively young patients. Conventional treatment options such as surgery and endovascular therapy often are insufficient for cure. There is a growing body of knowledge on the genetic and molecular underpinnings of AVM development and maintenance, making the future of precision medicine a real possibility for AVM management. Here, we review the pathophysiology of AVM development across various cell types, with a focus on current and potential druggable targets and their therapeutic potentials in both sporadic and familial AVM populations. Full article
(This article belongs to the Special Issue Vascular Malformation: From Pathophysiology, Clinical Manifestations to Novel Therapeutic Approaches)
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32 pages, 2330 KiB  
Review
The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations
by Ashley R. Ricciardelli, Ariadna Robledo, Jason E. Fish, Peter T. Kan, Tajie H. Harris and Joshua D. Wythe
Biomedicines 2023, 11(11), 2876; https://doi.org/10.3390/biomedicines11112876 - 24 Oct 2023
Cited by 4 | Viewed by 2697
Abstract
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. These high-flow, low-resistance shunts are composed of dilated, tortuous, and fragile vessels, [...] Read more.
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. These high-flow, low-resistance shunts are composed of dilated, tortuous, and fragile vessels, which are prone to rupture. BAVMs are a leading cause of hemorrhagic stroke in children and young adults. Current treatments for bAVMs are limited to surgery, embolization, and radiosurgery, although even these options are not viable for ~20% of AVM patients due to excessive risk. 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. We conclude by proposing that a dysfunctional endothelium, which harbors the somatic mutations that have been shown to give rise to sporadic bAVMs, may drive disease development and progression by altering the immune status of the brain. Full article
(This article belongs to the Special Issue Vascular Malformation: From Pathophysiology, Clinical Manifestations to Novel Therapeutic Approaches)
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