Polymorphisms in Transforming Growth Factor-β-Related Genes
            <i>ALK1</i>
            and
            <i>ENG</i>
            Are Associated With Sporadic Brain Arteriovenous Malformations

Pawlikowska, Ludmila; Tran, Mary N.; Achrol, Achal S.; Ha, Connie; Burchard, Esteban G.; Choudhry, Shweta; Zaroff, Jonathan G.; Lawton, Michael T.; Castro, Richard A.; McCulloch, Charles E.; Marchuk, Douglas A.; Kwok, Pui‐Yan; Young, William L.

doi:10.1161/01.str.0000182253.91167.fa

Cited by 80 publications

(58 citation statements)

References 8 publications

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“…SNPs of certain angiogenic factors were first associated with sporadic cerebral AVMs and subsequently with their risk of rupture. 37 Some specific molecules affected by SNPs are TGF-b, an extracellular glycosylated protein that suppresses the effects of interleukins and is critical in de novo AVM formation; 32 brain-derived neurotrophic factor (BDNF), a protein that supports survival, development, and function of neurons; 55 interleukin-6 (IL-6), which contributes to vascular wall instability by stimulating the release of MMP; 32,33,38 and angiopoietin-like 4 (ANGPTL4), a glycoprotein believed to be involved in angiogenesis (Table 1). 31 Vascular endothelial growth factor is a critical signaling molecule that regulates angiogenesis and is typically suppressed in normal adult vasculature.…”

Section: Avm Formationmentioning

confidence: 99%

Molecular and cellular biology of cerebral arteriovenous malformations: a review of current concepts and future trends in treatment

Rangel-Castilla¹,

Russin²,

Martinez-del-Campo³

et al. 2014

FOC

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Object Arteriovenous malformations (AVMs) are classically described as congenital static lesions. However, in addition to rupturing, AVMs can undergo growth, remodeling, and regression. These phenomena are directly related to cellular, molecular, and physiological processes. Understanding these relationships is essential to direct future diagnostic and therapeutic strategies. The authors performed a search of the contemporary literature to review current information regarding the molecular and cellular biology of AVMs and how this biology will impact their potential future management. Methods A PubMed search was performed using the key words “genetic,” “molecular,” “brain,” “cerebral,” “arteriovenous,” “malformation,” “rupture,” “management,” “embolization,” and “radiosurgery.” Only English-language papers were considered. The reference lists of all papers selected for full-text assessment were reviewed. Results Current concepts in genetic polymorphisms, growth factors, angiopoietins, apoptosis, endothelial cells, pathophysiology, clinical syndromes, medical treatment (including tetracycline and microRNA-18a), radiation therapy, endovascular embolization, and surgical treatment as they apply to AVMs are discussed. Conclusions Understanding the complex cellular biology, physiology, hemodynamics, and flow-related phenomena of AVMs is critical for defining and predicting their behavior, developing novel drug treatments, and improving endovascular and surgical therapies.

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Section: Avm Formationmentioning

confidence: 99%

Molecular and cellular biology of cerebral arteriovenous malformations: a review of current concepts and future trends in treatment

Rangel-Castilla¹,

Russin²,

Martinez-del-Campo³

et al. 2014

FOC

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“…59 The highly elevated risk of BAVM development among HHT patients suggests that germline variants of genes relating to these pathways could exert influence over risk for development of sporadic BAVMs. In fact, a common polymorphism in ALK1, thought to result in alternative splicing, has been associated with sporadic BAVM susceptibility, 74 suggesting that genetic variation in genes mutated in heritable BAVM syndromes may play a role in sporadic BAVMs. Furthermore, recent evidence suggests that ALK1 is associated with vascular remodeling and arterialization in response to hemodynamic changes, 81 and loss of function of this gene results in loss of distinct arterial and venous boundaries in mice.…”

Section: Genetic Considerationsmentioning

confidence: 99%

Pathogenesis and radiobiology of brain arteriovenous malformations: implications for risk stratification in natural history and posttreatment course

Achrol¹,

Guzman²,

Varga³

et al. 2009

FOC

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Brain arteriovenous malformations (BAVMs) are an important cause of intracerebral hemorrhage (ICH) in young adults. Biological predictors of future ICH risk are lacking, and controversy exists over previous studies of natural history risk among predominantly ruptured BAVM cohorts. Recent studies have suggested that the majority of BAVMs are now diagnosed as unruptured lesions, and that the risk according to natural history among these lesions may be less than previously assumed. In the first part of this review, the authors discuss available data on the natural history of BAVMs and highlight the need for future studies that aim to develop surrogate biomarkers of disease progression that accurately predict future risk of ICH in BAVMs. The etiology of BAVM remains unknown. Recent studies have suggested a role for genetic factors in the pathogenesis of sporadic BAVM, which is further supported by reports of familial occurrence of BAVM and association with known systemic genetic disorders (such as Osler-Weber-Rendu disease, Sturge-Weber disease, and Wyburn-Mason syndrome). Molecular characterization of BAVM tissue demonstrates a highly angiogenic milieu with evidence of increased endothelial cell turnover. Taken together with a number of reports of de novo BAVM formation, radiographic growth after initial BAVM diagnosis, and regrowth after successful treatment of BAVM, these findings challenge the long-held assumption that BAVMs are static lesions of congenital origin. In the second part of this review, the authors discuss available data on the origins of BAVM and offer insights into future investigations into genetics and endothelial progenitor cell involvement in the pathogenesis of BAVM. Current treatment options for BAVM focus on removal or obliteration of the lesion in an attempt to protect against future ICH risk, including microsurgical resection, endovascular embolization, and stereotactic radiosurgery (SRS). In the third part of this review, the authors discuss available data on SRS in BAVMs and highlight the need for future studies on the radiobiology of BAVMs, especially in regard to biomarker detection for tracking SRS response during the latency period. Insights from future investigations in BAVM may not only prove important for the development of novel therapies and relevant biomarkers for BAVM, but could also potentially benefit a variety of other disorders involving new vessel formation in the CNS, including stroke, tumors, moyamoya disease, and other cerebrovascular malformations.

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“…This disorder has a high penetrance, and patients present with multiple telangiectasias and arteriovenous malformations/fistulae (AVM/AVFs) [2]. The genetic mutations involve genes from the transforming growth factor (TGF) beta/bone morphogenic protein (BMP) superfamily, such as ENG (endoglin) and ALK-1 (activin receptor-like kinase) [3]. These genes are important in angiogenesis, and hence these patients develop mucocutaneous telangiectasias (including lips, tongue, oral cavity, and nose) and visceral AVMs (gastrointestinal, pulmonary, hepatic, cerebral, and spinal).…”

Section: Introductionmentioning

confidence: 99%

Use of Fluorescent Indocyanine Green Angiography During Microsurgical Resection of a Recurrent Giant Perimedullary Cervical Spinal Arteriovenous Fistula in a Patient with Hereditary Hemorrhagic Telangiectasia: A Case Report

Choudhri¹,

Heit²,

Gupta³

et al. 2014

Cureus

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We report the utility of fluorescent indocyanine green (ICG) during the microsurgical resection of a giant perimedullary cervical arteriovenous fistula (GPMAVF) in a young man with hereditary hemorrhagic telangiectasia. ICG angiography is a useful adjunct for understanding angioarchitecture and drainage patterns in spinal arteriovenous malformation (AVM) surgery. Cervical GPMAVF is a rare spinal lesion found in association with hereditary hemorrhagic telangiectasia. This vascular malformation is associated with venous varices in a perimedullary location causing cord compression and vascular steal. This rare case highlights the crucial role of ICG during complex spinal AVM/AVF surgery to obtain angiographic cure.

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Polymorphisms in Transforming Growth Factor-β-Related Genes ALK1 and ENG Are Associated With Sporadic Brain Arteriovenous Malformations

Cited by 80 publications

References 8 publications

Molecular and cellular biology of cerebral arteriovenous malformations: a review of current concepts and future trends in treatment

Molecular and cellular biology of cerebral arteriovenous malformations: a review of current concepts and future trends in treatment

Pathogenesis and radiobiology of brain arteriovenous malformations: implications for risk stratification in natural history and posttreatment course

Use of Fluorescent Indocyanine Green Angiography During Microsurgical Resection of a Recurrent Giant Perimedullary Cervical Spinal Arteriovenous Fistula in a Patient with Hereditary Hemorrhagic Telangiectasia: A Case Report

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