Biomedicines

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Special Issue Editors

Dr. Hua Su

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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

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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

Published Papers (2 papers)

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Research

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14 pages, 6581 KiB

Open AccessArticle

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

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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 postnatal window in which deletion of the HHT gene Endoglin (Eng) triggers BAVM development. We employed SclCreER(+);Eng^2f/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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32 pages, 2330 KiB

Open AccessReview

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

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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, 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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