Aberrant Angiogenic Characteristics of Human Brain Arteriovenous Malformation Endothelial Cells

Jabbour, Mark N.; Elder, J. Bradley; Samuelson, Christian G.; Khashabi, Shabnam; Hofman, Florence M.; Giannotta, Steven L.; Liu, Charles Y.

doi:10.1227/01.neu.0000334417.56742.24

Cited by 78 publications

(68 citation statements)

References 30 publications

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“…In contrast, later true recurrences may be explained by a potential for proliferation in the immature microvessel network, as supported by the detection of endothelial progenitor markers (CD31, CD34, and CD105) in resected AVM. 33 Age was recognized as a major risk factor for bAVM recurrence, with a 63% recurrence rate at 10 years for patients <20 years of age. 34 Therefore, a long-term imaging follow-up is recommended in pediatric AVM.…”

Section: June 2014mentioning

confidence: 99%

Long-Term Outcome of 106 Consecutive Pediatric Ruptured Brain Arteriovenous Malformations After Combined Treatment

Blauwblomme

Bourgeois

Meyer

et al. 2014

Stroke

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Background and Purpose-Childhood intracerebral hemorrhage is mainly attributable to underlying brain arteriovenous malformations (bAVMs). Multimodal treatment options for bAVMs include microsurgery and embolization, allowing an immediate cure, and radiosurgery, entailing longer obliteration times. Follow-up data on pediatric ruptured bAVMs are scarce, making it difficult to assess the risk of subsequent intracerebral hemorrhage. Our aim was to assess the clinical and angiographic outcome and to analyze risk factors for rebleeding during and after combined treatment of pediatric bAVMs. Methods-A prospectively maintained database of children referred to our institution between January 1997 and October 2012 for bAVMs was retrospectively queried to identify all consecutive ruptured bAVMs treated by surgery, embolization, and radiosurgery. The impact of baseline clinical and bAVM characteristics on clinical outcome, rebleeding rate, annual bleeding rate, and bAVM obliteration was studied using univariate and multivariate Cox regression analysis. Results-One hundred six children with ruptured bAVMs were followed up for a total of 480.5 patient-years (mean, 4.5 years). Thirteen rebleeding events occurred, corresponding to an annual bleeding rate of 2.71±1.32%, significantly higher in the first year (3.88±1.39%) than thereafter (2.22±1.38%; P<0.001) and in the case of associated aneurysms (relative risk, 2.68; P=0.004) or any deep venous drainage (relative risk, 2.97; P=0.002), in univariate and multivariate analysis. Partial embolization was associated with a higher annual bleeding rate, whereas initial surgery for intracerebral hemorrhage evacuation was associated with a lower risk of rebleeding. Conclusions-Associated aneurysms and any deep venous drainage are independent risk factors for rebleeding in pediatric ruptured bAVMs. Immediate surgery or total embolization might be advantageous for children harboring such characteristics, whereas radiosurgery might be targeted at patients without such characteristics. (Stroke. 2014;45:1664-1671.)

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Section: June 2014mentioning

confidence: 99%

Long-Term Outcome of 106 Consecutive Pediatric Ruptured Brain Arteriovenous Malformations After Combined Treatment

Blauwblomme

Bourgeois

Meyer

et al. 2014

Stroke

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“…AVM-BECs proliferate more rapidly, migrate faster, and produce aberrant tubule structures. 3 AVM-BECs also express low levels of thrombospondin-1 (TSP-1), a key regulator of angiogenesis. TSP-1 treatment or silencing of one of its transcriptional repressors, inhibitor of DNA-binding protein 1 (Id-1), brings AVM-BECs to more normal rates of proliferation, migration, and tubule formation efficacy.…”

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confidence: 99%

“…4 Moreover, TSP-1 antagonizes a key proangiogenic factor, vascular endothelial growth factor A (VEGF-A), 5 which is expressed at higher levels in AVM-BECs as compared with control BECs. 3 MicroRNAs (miRNAs) are small noncoding RNAs that inhibit gene expression by targeting messenger RNA for cleavage or translational repression. In this study, we used microRNA-18a (miR-18a) to inhibit Id-1 expression, thereby increasing TSP-1 release to normalize several of the reported aberrant features of AVM-BECs.…”

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confidence: 99%

MicroRNA-18a Improves Human Cerebral Arteriovenous Malformation Endothelial Cell Function

Ferreira

Santos

Amar

et al. 2014

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Background and Purpose-Cerebral arteriovenous malformation (AVM) is a vascular disease that disrupts normal blood flow and leads to serious neurological impairment or death. Aberrant functions of AVM-derived brain endothelial cells (AVM-BECs) are a disease hallmark. Our aim was to use microRNA-18a (miR-18a) as a therapeutic agent to improve AVM-BEC function. Methods-Human AVM-BECs were tested for growth factor production and proliferation under different shear flow conditions and evaluated for tubule formation. Thrombospondin-1, inhibitor of DNA-binding protein 1, and vascular endothelial growth factor (VEGF) isotype mRNA levels were quantified by quantitative real-time polymerase chain reaction. Thrombospondin-1, VEGF-A, and VEGF-D protein expression was measured using enzyme-linked immunosorbent assay. Proliferation and tubule formation were evaluated using bromodeoxyuridine incorporation and growth factor-reduced Matrigel assays, respectively. Results-miR-18a increased thrombospondin-1 production but decreased inhibitor of DNA-binding protein 1, a transcriptional repressor of thrombospondin-1. miR-18a reduced VEGF-A and VEGF-D levels, both overexpressed in untreated AVM-BECs. This is the first study reporting VEGF-D overexpression in AVM. These effects were most prominent under arterial shear flow conditions. miR-18a also reduced AVM-BEC proliferation, improved tubule formation, and was effectively internalized by AVM-BECs in the absence of extraneous transfection reagents. Conclusions-We

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“…Several investigations on cerebral AVMs in general revealed overexpression of the vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2 on endothelial cells in patients with cerebral AVMs. 11 VEGF is a signal protein that plays a key…”

Section: Discussionmentioning

confidence: 99%

Caroli Disease Associated With Vein of Galen Malformation in a Male Child

et al. 2014

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We report the first case of a male child with both Caroli disease and vein of Galen malformation. The neonate presented to our department with congestive heart failure as a result of the intracranial arteriovenous high-flow shunt. Over time, several endovascular embolizations led to a complete angiographic occlusion of the shunt. Additionally, the diagnosis of Caroli disease was made at the age of 2 months. He developed choledocholithiasis necessitating endoscopic sphincterotomy and stone extraction. As a prolonged medical treatment he received ursodeoxycholic acid and antibiotics. A coincidence of Caroli disease and vein of Galen malformation has not yet been described. Both diseases are very rare, leading to the question of whether there is a link in the pathogenesis. Based on the few previously described underlying mechanisms, we develop hypotheses about the relationship between both rare diseases. We consider overexpression of vascular endothelial growth factor and its receptors as a possible common molecular mechanism in their pathogenesis. We also highlight the critical role of increased expression of the Notch ligand Jagged 1 both in the development of cerebral arteriovenous malformations in general and in the formation of dilated intrahepatic bile ducts (eg, in Caroli disease).

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Aberrant Angiogenic Characteristics of Human Brain Arteriovenous Malformation Endothelial Cells

Abstract: Endothelial cells derived from cerebral AVMs are highly activated cells overexpressing proangiogenic growth factors and exhibiting abnormal functions consistent with highly activated endothelial cells.

Cited by 78 publications

References 30 publications

Long-Term Outcome of 106 Consecutive Pediatric Ruptured Brain Arteriovenous Malformations After Combined Treatment

Long-Term Outcome of 106 Consecutive Pediatric Ruptured Brain Arteriovenous Malformations After Combined Treatment

MicroRNA-18a Improves Human Cerebral Arteriovenous Malformation Endothelial Cell Function

Caroli Disease Associated With Vein of Galen Malformation in a Male Child

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