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Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo.

ABSTRACT: Abnormalities in arterial versus venous endothelial cell identity and dysregulation of angiogenesis are deemed important in the pathophysiology of brain arteriovenous malformations (AVMs). The Sonic hedgehog (Shh) pathway is crucial for both angiogenesis and arterial versus venous differentiation of endothelial cells, through its dual role on the vascular endothelial growth factor/Notch signaling and the nuclear orphan receptor COUP-TFII. In this study, we show that Shh, Gli1 (the main transcription factor of the Shh pathway), and COUP-TFII (a target of the non-canonical Shh pathway) are aberrantly expressed in human brain AVMs. We also show that implantation of pellets containing Shh in the cornea of Efnb2/LacZ mice induces growth of distinct arteries and veins, interconnected by complex sets of arteriovenous shunts, without an interposed capillary bed, as seen in AVMs. We also demonstrate that injection in the rat brain of a plasmid containing the human Shh gene induces the growth of tangles of tortuous and dilated vessels, in part positive and in part negative for the arterial marker αSMA, with direct connections between αSMA-positive and -negative vessels. In summary, we show that the Shh pathway is active in human brain AVMs and that Shh-induced angiogenesis has characteristics reminiscent of those seen in AVMs in humans.

SUBMITTER: Giarretta I

PROVIDER: S-EPMC8369994 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo.

Giarretta Igor I Sturiale Carmelo L CL Gatto Ilaria I Pacioni Simone S Gaetani Eleonora E Porfidia Angelo A Puca Alfredo A Palucci Ivana I Tondi Paolo P Olivi Alessandro A Pallini Roberto R Pola Roberto R

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20200313 2

Abnormalities in arterial versus venous endothelial cell identity and dysregulation of angiogenesis are deemed important in the pathophysiology of brain arteriovenous malformations (AVMs). The Sonic hedgehog (Shh) pathway is crucial for both angiogenesis and arterial versus venous differentiation of endothelial cells, through its dual role on the vascular endothelial growth factor/Notch signaling and the nuclear orphan receptor COUP-TFII. In this study, we show that Shh, Gli1 (the main transcrip ...[more]

PMID: 32169015

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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.

Dataset Information

Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo.

Publications

Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo.

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