Radiosurgery inhibition of the Notch signaling pathway in a rat model of arteriovenous malformations

Tu, Jian; Li, Yang; Hu, Zhiqiang; Chen, Zhongbin

doi:10.3171/2013.12.jns131595

Cited by 10 publications

(5 citation statements)

References 72 publications

(100 reference statements)

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“…Yu et al (46) recently reported that the activation of Notch1 and Hes1 is instrumental in withstanding myocardial I/R injury. Tu et al (47) previously demonstrated that the activated Notch signaling pathway has been involved in the arteriovenous lesions in mice in accordance with the present conjecture. The present findings suggested that the activation of the Notch pathway upregulated the eNOS expression and NO production and alleviated cerebral ischemic injury, resulting in cerebrovascular pathology and neurological disease.…”

Section: Discussionsupporting

confidence: 92%

microRNA‑155 induces protection against cerebral ischemia/reperfusion injury through regulation of the Notch pathway in�vivo

Jiang

Zhou

et al. 2019

Exp Ther Med

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microRNA (miR)-155 has been demonstrated to participate in the regulation of endothelium during cerebral ischemia. In the present study, it was aimed to investigate the molecular mechanism of miR-155 in the regulation of cerebral ischemia/reperfusion (I/R) injury with middle cerebral artery occlusion (MCAO) in mice. The MCAO model was established in C57BL/6 mice. Transfection of miR-155 mimics and miR-155 inhibitors was performed to alter the expression of miR-155. The level of miR-155 was measured by RT-qPCR analysis. The western blotting results demonstrated that deletion of miR-155 increased the expression of Notch1, intracellular Notch receptor domain (NICD) and hairy and enhancer of split-1 (Hes1) levels. In addition, the percentage of terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling-positive cells and caspase-3 levels were decreased following treatment with a miR-155 inhibitor compared with the Pre-IR group. Notably, disrupting miR-155 also increased nitric oxide (NO) production and the expression of endothelial NO synthase (eNOS), leading to downregulation of brain water content and Evans blue levels. However, overexpression of miR-155 restored all these changes to similar levels observed in the cerebral I/R injury group. The expressions of Notch1, NICD and Hes1 were also decreased to the cerebral I/R injury condition. In conclusion, a novel mechanism was identified for abrogating normal NO production and eNOS expression via the aberrant expression of the Notch signaling pathway, a mechanism that may be modulated by miR-155. Together, these results reveal important functions of miR-155 in regulating the Notch signaling pathway of the nervous system, and a potential role for miR-155 as a crucial therapy target for cerebral stroke.

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Section: Discussionsupporting

confidence: 92%

microRNA‑155 induces protection against cerebral ischemia/reperfusion injury through regulation of the Notch pathway in�vivo

Jiang

Zhou

et al. 2019

Exp Ther Med

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“…Germline mutations in VOGM risk genes RASA1, EPHB4, ACVRL1, PTNPN11, and NOTCH1 have been reported in other Mendelian diseases featuring vascular phenotypes 25,27,109,110,[114][115][116] . RASA1 and EPHB4 encode interacting proteins mutated in CM-AVM type 1 and 2, respectively.…”

Section: Discussionmentioning

confidence: 99%

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

Zhao

Mekbib

Ent

et al. 2023

Preprint

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To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79x10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (p=1.22x10-5), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a second-hit allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

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“…In terms of emerging molecular targets in AVM, radiosurgery is seen to both induce thrombotic occlusion of nidus vessels in addition to inhibiting Notch1 and Notch4 signaling in endothelial cells [ 66 ]. Both increased and decreased Notch activity induce AVM formation in sporadic AVM and syndromic-type Alk1 knockout models, respectively [ 21 , 67 , 68 ].…”

Section: Discussionmentioning

confidence: 99%

Intermixed arteriovenous malformation and hemangioblastoma: case report and literature review

et al. 2020

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We report the third presentation of an intermixed arteriovenous malformation and hemangioblastoma. The rare occurrence of the diagnostic histologic features of both a neoplasm and vascular malformation in a single lesion is more common in gliomas, as angioglioma, and is termed an 'intermixed’ lesion. We review the literature concerning the developmental biology of each lesion, and potential interplay in the formation of an intermixed vascular neoplasm and vascular malformation. The roles of cellular origin, genetic susceptibility, favourable microenvironment, altered local gene expression and key regulatory pathways are reviewed. Our review supports angiography and genetic profiling in intermixed lesions to inform management strategies. Consideration should be given to multimodality therapeutic interventions as required, including microsurgical resection, stereotactic radiosurgery and further research to exploit emerging molecular targets.

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Radiosurgery inhibition of the Notch signaling pathway in a rat model of arteriovenous malformations

Cited by 10 publications

References 72 publications

microRNA‑155 induces protection against cerebral ischemia/reperfusion injury through regulation of the Notch pathway in�vivo

microRNA‑155 induces protection against cerebral ischemia/reperfusion injury through regulation of the Notch pathway in�vivo

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

Intermixed arteriovenous malformation and hemangioblastoma: case report and literature review

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