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RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations.

ABSTRACT: Background The blood flow rate of brain arteriovenous malformations ( bAVM s) is an important clinical characteristic closely associated with the hemorrhage risk and radiosurgery obliteration rate of bAVM s. However, the underlying molecular properties remain unclear. To identify potential key molecules, signaling pathways, and vascular cell types involved, we compared gene expression profiles between bAVM s with high flow rates and low flow rates ( LFR ) and validated the functions of selected key molecules in vitro. Methods and Results We performed RNA -sequencing analysis on 51 samples, including 14 high flow rate bAVM s and 37 LFR bAVM s. Functional pathway analysis was performed to identify potential signals influencing the flow rate phenotype of bAVM s. Candidate genes were investigated in bAVM specimens by immunohistochemical staining. Migration, tube formation, and proliferation assays were used to test the effects of candidate genes on the phenotypic properties of cultured human umbilical vein endothelial cells and human brain vascular smooth muscle cells. We identified 250 upregulated and 118 downregulated genes in LFR bAVM s compared with high flow rate bAVM s. Wnt signaling was activated in the LFR group via upregulation of FZD 10 and MYOC . Immunohistochemical staining showed that vascular endothelial and smooth muscle cells of LFR bAVM s exhibited increased FZD 10 and MYOC expression. Experimentally elevating these genes promoted human umbilical vein endothelial cells and migration and tube formation by activating canonical Wnt signaling in vitro. Conclusions Our results suggest that canonical Wnt signaling mediated by FZD 10 and MYOC is activated in vascular endothelial and smooth muscle cells in LFR bAVM s.

SUBMITTER: Huo R

PROVIDER: S-EPMC6645621 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations.

Huo Ran R Fu Weilun W Li Hao H Jiao Yuming Y Yan Zihan Z Wang Linjian L Wang Jie J Wang Shuo S Cao Yong Y Zhao Jizong J

Journal of the American Heart Association 20190607 12

Background The blood flow rate of brain arteriovenous malformations ( bAVM s) is an important clinical characteristic closely associated with the hemorrhage risk and radiosurgery obliteration rate of bAVM s. However, the underlying molecular properties remain unclear. To identify potential key molecules, signaling pathways, and vascular cell types involved, we compared gene expression profiles between bAVM s with high flow rates and low flow rates ( LFR ) and validated the functions of selected ...[more]

PMID: 31170876

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Project description:BackgroundBrain arteriovenous malformations (AVMs) are the single most common cause of intracerebral haemorrhage in young adults. Brain AVMs also cause seizure(s) and focal neurological deficits (in the absence of haemorrhage, migraine or an epileptic seizure); approximately one-fifth are incidental discoveries. Various interventions are used in an attempt to eradicate brain AVMs: neurosurgical excision, stereotactic radiosurgery, endovascular embolization, and staged combinations of these interventions. This is an update of a Cochrane Review first published in 2006, and last updated in 2009.ObjectivesTo determine the effectiveness and safety of the different interventions, alone or in combination, for treating brain AVMs in adults compared against either each other, or conservative management, in randomized controlled trials (RCTs).Search methodsThe Cochrane Stroke Group Information Specialist searched the Cochrane Stroke Group Trials Register (last searched 7 January 2019), the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 1) in the Cochrane Library, MEDLINE Ovid (1980 to 14 January 2019), and Embase OVID (1980 to 14 January 2019). We searched international registers of clinical trials, the contents pages of relevant journals, and bibliographies of relevant articles (November 2009). We also contacted manufacturers of interventional treatments for brain AVMs (March 2005).Selection criteriaWe sought RCTs of any intervention for brain AVMs (used alone or in combination), compared against each other or against conservative management, with relevant clinical outcome measures.Data collection and analysisOne author screened the results of the updated searches for potentially eligible RCTs for this updated review. Both authors independently read the potentially eligible RCTs in full and confirmed their inclusion according to the inclusion criteria. We resolved disagreement by discussion. We assessed the risk of bias in included studies and applied GRADE.Main resultsWe included one trial with 226 participants: A Randomized trial of Unruptured Brain Arteriovenous Malformations (ARUBA), comparing intervention versus conservative management for unruptured brain AVMs (that had never bled). The quality of evidence was moderate because we found just one trial that was at low risk of bias other than a high risk of performance bias due to participants and treating physicians not being blinded to allocated treatment. Data on functional outcome and death at a follow-up of 12 months were provided for 218 (96%) of the participants in ARUBA. In this randomized controlled trial (RCT), intervention compared to conservative management increased death or dependency (modified Rankin Scale score ≥ 2, risk ratio (RR) 2.53, 95% confidence interval (CI) 1.28 to 4.98; 1 trial, 226 participants; moderate-quality evidence) and the proportion of participants with symptomatic intracranial haemorrhage (RR 6.75, 95% CI 2.07 to 21.96; 1 trial, 226 participants; moderate-quality evidence), but there was no difference in the frequency of epileptic seizures (RR 1.14, 95% CI 0.63 to 2.06; 1 trial, 226 participants; moderate-quality evidence). Three RCTs are ongoing.Authors' conclusionsWe found moderate-quality evidence from one RCT including adults with unruptured brain AVMs that conservative management was superior to intervention with respect to functional outcome and symptomatic intracranial haemorrhage over one year after randomization. More RCTs will help to confirm or refute these findings.

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RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations.

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RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations.

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