Propranolol Reduces the Development of Lesions and Rescues Barrier Function in Cerebral Cavernous Malformations

Background and Purpose: Cerebral cavernous malformations (CCM) present as mulberry-like malformations of the microvasculature of the central nervous system. Current medical treatment of CCM lesions is limited to surgical removal of the vascular malformations. It is, therefore, important to identify therapeutic drug treatments for patients with CCM. Propranolol has shown great benefit in the treatment of infantile hemangioma. In addition, patients with CCM who receive propranolol have demonstrated a reduction of their lesions. Our investigation set out to provide preclinical data to support propranolol as a therapeutic treatment. Methods: An inducible endothelial-specific Ccm3 knockout murine model (CCM3 iECKO ) was used, with assessment of lesion quantity and size following oral treatment with propranolol. Scanning and transmission electron microscopy were used to characterize the CCM3 iECKO lesions and the effects of propranolol on the disease. Immunofluorescent imaging was used to investigate pericyte coverage in the propranolol-treated CCM3 iECKO mice. Results: With propranolol treatment, the lesion quantity, size, and volume decreased in both the brain and retina in the CCM3 iECKO model. Novel characteristics of the CCM3 iECKO lesions were discovered using electron microscopy, including plasmalemmal pits and thickening of the endothelial-pericyte basal membrane. These characteristics were absent with propranolol treatment. Pericyte coverage of the CCM3 iECKO lesions increased after propranolol treatment, and vascular leakage was reduced. Conclusions: This study supports the concept that propranolol can be used to reduce and stabilize vascular lesions and can, therefore, be suggested as a pharmaceutical treatment for CCM.

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Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

Journal of Experimental Medicine ◽

10.1084/jem.20110571 ◽

2011 ◽

Vol 208 (9) ◽

pp. 1835-1847 ◽

Cited By ~ 78

Author(s):

Gwénola Boulday ◽

Noemi Rudini ◽

Luigi Maddaluno ◽

Anne Blécon ◽

Minh Arnould ◽

...

Keyword(s):

Autosomal Dominant ◽

Vascular Malformations ◽

Vascular Lesions ◽

Developmental Timing ◽

Cerebral Cavernous Malformations ◽

Loss Of Function ◽

Cavernous Malformations ◽

The Central Nervous System ◽

Dominant Condition

Cerebral cavernous malformations (CCM) are vascular malformations of the central nervous system (CNS) that lead to cerebral hemorrhages. Familial CCM occurs as an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. Constitutive or tissue-specific ablation of any of the Ccm genes in mice previously established the crucial role of Ccm gene expression in endothelial cells for proper angiogenesis. However, embryonic lethality precluded the development of relevant CCM mouse models. Here, we show that endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice results in vascular lesions mimicking human CCM lesions. Consistent with CCM1/3 involvement in the same human disease, deletion of Ccm1/3 at P1 in mice results in similar CCM lesions. The lesions are located in the cerebellum and the retina, two organs undergoing intense postnatal angiogenesis. Despite a pan-endothelial Ccm2 deletion, CCM lesions are restricted to the venous bed. Notably, the consequences of Ccm2 loss depend on the developmental timing of Ccm2 ablation. This work provides a highly penetrant and relevant CCM mouse model.

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Cerebral Cavernous Malformations, Developmental Venous Anomaly, and Its Coexistence: A Review

European Neurology ◽

10.1159/000508748 ◽

2020 ◽

Vol 83 (4) ◽

pp. 360-368 ◽

Cited By ~ 1

Author(s):

Pretty Sara Idiculla ◽

Dhineshreddy Gurala ◽

Jobin Philipose ◽

Kartikeya Rajdev ◽

Prateek Patibandla

Keyword(s):

English Language ◽

Vascular Malformations ◽

Incidental Finding ◽

Neurological Deficits ◽

Vascular Lesions ◽

Cerebral Cavernous Malformations ◽

Developmental Venous Anomaly ◽

Venous Anomaly ◽

Cavernous Malformations ◽

Acute Thrombosis

Background: Cerebral cavernous malformations (CCMs) are intracranial vascular malformations that can exist as a single lesion or mixed vascular lesions. The most common mixed form is the coexistence of CCM with an associated developmental venous anomaly (DVA). In this paper, we aim to give a comprehensive review of CCM, DVA, and their coexistence as mixed lesions. A PubMed search using the keywords “Cerebral cavernous malformations, Developmental venous anomaly, Mixed Cerebral cavernous malformations with Developmental venous anomaly” was done. All studies in the English language in the past 10 years were analyzed descriptively for this review. Summary: The search yielded 1,249 results for “Cerebral cavernous malformations,” 271 results for “Developmental venous anomaly,” and 5 results for “Mixed Cerebral cavernous malformations with Developmental venous anomaly.” DVA is the most common intracranial vascular malformation, followed by CCM. CCM can have a wide array of clinical presentations like hemorrhage, seizures, or focal neurological deficits or can also be an incidental finding on brain imaging. DVAs are benign lesions by nature; however, venous infarction can occur in a few patients due to acute thrombosis. Mixed CCM with DVA has a higher risk of hemorrhage. CCMs are angiographically occult lesion, and cerebral digital subtraction angiography is the gold standard for the diagnosis of DVA. Mixed lesions, on the other hand, are best diagnosed with magnetic resonance imaging, which has also been effective in detecting specific abnormalities. Asymptomatic lesions are treated through a conservative approach, while clinically symptomatic lesions need surgical management. Conclusion: Individual CCM or DVA lesions have a benign course; however, when they coexist in the same individual, the hemorrhagic risk is increased, which prompts for rapid diagnosis and treatment.

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Transcriptome-wide Profiling of Cerebral Cavernous Malformations Patients Reveal Important Long noncoding RNA molecular signatures

Scientific Reports ◽

10.1038/s41598-019-54845-0 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Santhilal Subhash ◽

Norman Kalmbach ◽

Florian Wegner ◽

Susanne Petri ◽

Torsten Glomb ◽

...

Keyword(s):

Noncoding Rna ◽

Vascular Malformations ◽

Cerebrovascular Disorders ◽

Gene Set Enrichment Analysis ◽

Differentially Expressed ◽

Low Flow ◽

Pcr Analysis ◽

Cerebral Cavernous Malformations ◽

Cavernous Malformations ◽

Non Coding Rnas

AbstractCerebral cavernous malformations (CCMs) are low-flow vascular malformations in the brain associated with recurrent hemorrhage and seizures. The current treatment of CCMs relies solely on surgical intervention. Henceforth, alternative non-invasive therapies are urgently needed to help prevent subsequent hemorrhagic episodes. Long non-coding RNAs (lncRNAs) belong to the class of non-coding RNAs and are known to regulate gene transcription and involved in chromatin remodeling via various mechanism. Despite accumulating evidence demonstrating the role of lncRNAs in cerebrovascular disorders, their identification in CCMs pathology remains unknown. The objective of the current study was to identify lncRNAs associated with CCMs pathogenesis using patient cohorts having 10 CCM patients and 4 controls from brain. Executing next generation sequencing, we performed whole transcriptome sequencing (RNA-seq) analysis and identified 1,967 lncRNAs and 4,928 protein coding genes (PCGs) to be differentially expressed in CCMs patients. Among these, we selected top 6 differentially expressed lncRNAs each having significant correlative expression with more than 100 differentially expressed PCGs. The differential expression status of the top lncRNAs, SMIM25 and LBX2-AS1 in CCMs was further confirmed by qRT-PCR analysis. Additionally, gene set enrichment analysis of correlated PCGs revealed critical pathways related to vascular signaling and important biological processes relevant to CCMs pathophysiology. Here, by transcriptome-wide approach we demonstrate that lncRNAs are prevalent in CCMs disease and are likely to play critical roles in regulating important signaling pathways involved in the disease progression. We believe, that detailed future investigations on this set of identified lncRNAs can provide useful insights into the biology and, ultimately, contribute in preventing this debilitating disease.

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Are cavernous sinus hemangiomas and cavernous malformations different entities?

Neurosurgical FOCUS ◽

10.3171/foc.2006.21.1.7 ◽

2006 ◽

Vol 21 (1) ◽

pp. 1-5 ◽

Cited By ~ 42

Author(s):

L. Fernando Gonzalez ◽

Gregory P. Lekovic ◽

Jennifer Eschbacher ◽

Stephen Coons ◽

Randall W. Porter ◽

...

Keyword(s):

Cavernous Sinus ◽

Cavernous Malformation ◽

Vascular Malformations ◽

Response To Treatment ◽

Vascular Tumors ◽

Cerebral Cavernous Malformations ◽

Imaging Studies ◽

Cavernous Malformations ◽

Cavernous Hemangiomas

✓Cavernous hemangiomas that occur within the cavernous sinus (CS) are different from cerebral cavernous malformations (CMs) clinically, on imaging studies, and in their response to treatment. Moreover, CMs are true vascular malformations, whereas hemangiomas are benign vascular tumors. Because of these differences, the authors suggest that these two entities be analyzed and grouped separately. Unfortunately, despite these differences, much confusion exists in the literature as to the nature, behavior, and classification of these two distinct lesions. This confusion is exacerbated by subtle histological differences and the inconsistent use of nomenclature. The authors use the term “cavernous malformation” to refer to intraaxial lesions only; they prefer to use the term “cavernous sinus hemangioma” to refer to extraaxial, intradural hemangiomas of the CS.

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Modified classification of spinal cord vascular lesions

Journal of Neurosurgery Spine ◽

10.3171/spi.2002.96.2.0145 ◽

2002 ◽

Vol 96 (2) ◽

pp. 145-156 ◽

Cited By ~ 133

Author(s):

Robert F. Spetzler ◽

Paul W. Detwiler ◽

Howard A. Riina ◽

Randall W. Porter

Keyword(s):

Spinal Cord ◽

Classification System ◽

Arteriovenous Malformations ◽

Vascular Malformations ◽

Relevant Literature ◽

Vascular Lesions ◽

Cavernous Malformations ◽

Content Type ◽

Arteriovenous Fistulas ◽

Fine Print

The literature on spinal vascular malformations contains a great deal of confusing terminology. Some of the nomenclature is inconsistent with the lesions described. Based on the experience of the senior author (R.F.S.) in the treatment of more than 130 spinal cord vascular lesions and based on a thorough review of the relevant literature, the authors propose a modified classification system for spinal cord vascular lesions. Lesions are divided into three primary or broad categories: neoplasms, aneurysms, and arteriovenous lesions. Neoplastic vascular lesions include hemangioblastomas and cavernous malformations, both of which occur sporadically and familially. The second category consists of spinal aneurysms, which are rare. The third category, spinal cord arteriovenous lesions, is divided into arteriovenous fistulas and arteriovenous malformations (AVMs). Arteriovenous fistulas are subdivided into those that are extradural and those that are intradural, with intradural lesions categorized as either dorsal or ventral. Arteriovenous malformations are subdivided into extradural-intradural and intradural malformations. Intradural lesions are further divided into intramedullary, intramedullary-extramedullary, and conus medullaris, a new category of AVM. This modified classification system for vascular lesions of the spinal cord, based on pathophysiology, neuroimaging features, intraoperative observations, and neuroanatomy, offers several advantages. First, it includes all surgical vascular lesions that affect the spinal cord. Second, it guides treatment by classifying lesions based on location and pathophysiology. Finally, it eliminates the confusion produced by the multitude of unrelated nomenclatural terms found in the literature.

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A Novel CCM2 Missense Variant Caused Cerebral Cavernous Malformations in a Chinese Family

Frontiers in Neuroscience ◽

10.3389/fnins.2020.604350 ◽

2021 ◽

Vol 14 ◽

Author(s):

Guoqing Han ◽

Li Ma ◽

Huanhuan Qiao ◽

Lin Han ◽

Qiaoli Wu ◽

...

Keyword(s):

Vascular Malformations ◽

Case Reports ◽

Chinese Family ◽

Incomplete Penetrance ◽

Cerebral Cavernous Malformations ◽

Missense Mutations ◽

Inherited Disease ◽

Cavernous Malformations ◽

Direct Dna Sequencing ◽

Number Of Patients

Cerebral cavernous malformations (CCMs) are common vascular malformations in the central nervous system. Familial CCMs (FCCMs) are autosomal dominant inherited disease with incomplete penetrance and variable symptoms. Mutations in the KRIT1, CCM2, and PDCD10 genes cause the development of FCCM. Approximately 476 mutations of three CCM-related genes have been reported, most of which were case reports, and lack of data in stable inheritance. In addition, only a small number of causative missense mutations had been identified in patients. Here, we reported that 8/20 members of a Chinese family were diagnosed with CCMs. By direct DNA sequencing, we found a novel variant c.331G > C (p.A111P) in exon 4 of the CCM2 gene, which was a heterozygous exonic variant, in 7/20 family members. We consider this variant to be causative of disease due to a weaken the protein–protein interaction between KRIT1 and CCM2. In addition, we also found the exon 13 deletion in KRIT1 coexisting with the CCM2 mutation in patient IV-2, and this was inherited from her father (patient III-1H). This study of a Chinese family with a large number of patients with CCMs and stable inheritance of a CCM2 mutation contributes to better understanding the spectrum of gene mutations in CCMs.

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Role of sclerotherapy in management of low flow vascular malformations

International Surgery Journal ◽

10.18203/2349-2902.isj20211303 ◽

2021 ◽

Vol 8 (4) ◽

pp. 1234

Author(s):

Manpreet Kaur ◽

Parul Sachdeva ◽

Rajan Syal ◽

Savijot Singh

Keyword(s):

Head And Neck ◽

Vascular Malformations ◽

Neck Region ◽

Low Flow ◽

Vascular Lesions ◽

Surgical Removal ◽

Complete Regression ◽

Head And Neck Region ◽

Life Threatening

Background: Low flow vascular malformations are most common in the head and neck region. Only symptomatic malformations require treatment. Sclerotherapy followed by surgery was considered the gold standard treatment but in the head and neck region, it may produce cosmetic and physiological defects. In the present study, multiple injections of sclerotherapy with 3% sodium tetradecyl sulphate was used for the treatment of low flow vascular malformations.Methods: Twenty cases of low flow vascular malformations of the oral cavity who presented in the outpatient department of ESIC Model Hospital, Ludhiana from 2014-2016 were selected for the study. Only significantly sized (>4 cm) and easily accessible lesions were included. Staged sequential sclerotherapy with 3% STS under strict fluoroscopy control was used as the sole treatment.Results: A total of 20 patients were taken of which, 25% required three sessions, 65% five to six sessions each and 10% required eight sessions each. All patients showed good results with complete regression and no mucosal ulceration.Conclusions: Staged sequential sclerotherapy with 3% STS should be the treatment of choice in low flow vascular lesions involving mucosal and cutaneous structures of head and neck region especially anterior two-thirds of tongue, palate, gingiva, buccal mucosa and lips. Surgical removal may affect critical neurovascular structures and cause cosmetic deformity. So the removal is advisable in life-threatening conditions, lesions requiring general anaesthesia and single sitting removal.

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High Levels of Receptor Tyrosine Kinases in CCM3-Deficient Cells Increase Their Susceptibility to Tyrosine Kinase Inhibition

Biomedicines ◽

10.3390/biomedicines8120624 ◽

2020 ◽

Vol 8 (12) ◽

pp. 624

Author(s):

Miriam Sartages ◽

Ebel Floridia ◽

Mar García-Colomer ◽

Cristina Iglesias ◽

Manuel Macía ◽

...

Keyword(s):

Growth Factor ◽

Tyrosine Kinase ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Vascular Malformations ◽

Mrna Level ◽

Growth Factor Receptor ◽

Surgical Removal ◽

Cavernous Malformations ◽

Cellular Effects

Cerebral cavernous malformations (CCMs) are vascular malformations that can be the result of the deficiency of one of the CCM genes. Their only present treatment is surgical removal, which is not always possible, and an alternative pharmacological strategy to eliminate them is actively sought. We have studied the effect of the lack of one of the CCM genes, CCM3, in endothelial and non-endothelial cells. By comparing protein expression in control and CCM3-silenced cells, we found that the levels of the Epidermal Growth Factor Receptor (EGFR) are higher in CCM3-deficient cells, which adds to the known upregulation of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in these cells. Whereas VEGFR2 is upregulated at the mRNA level, EGFR has a prolonged half-life. Inhibition of EGFR family members in CCM3-deficient cells does not revert the known cellular effects of lack of CCM genes, but it induces significantly more apoptosis in CCM3-deficient cells than in control cells. We propose that the susceptibility to tyrosine kinase inhibitors of CCM3-deficient cells can be harnessed to kill the abnormal cells of these lesions and thus treat CCMs pharmacologically.

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Effective surgical treatment of cerebral cavernous malformations: a multicenter study of 79 pediatric patients

Journal of Neurosurgery Pediatrics ◽

10.3171/2011.8.peds09164 ◽

2011 ◽

Vol 8 (5) ◽

pp. 522-525 ◽

Cited By ~ 17

Author(s):

Michael Hugelshofer ◽

Nicola Acciarri ◽

Ulrich Sure ◽

Dimitrios Georgiadis ◽

Ralf W. Baumgartner ◽

...

Keyword(s):

Pediatric Patients ◽

Refractory Epilepsy ◽

Epileptic Seizures ◽

Neurological Deficits ◽

Vascular Lesions ◽

Cerebral Cavernous Malformations ◽

Cavernous Malformations ◽

Persistent Symptoms ◽

The Mean ◽

The Brain

Object Cerebral cavernous malformations (CCMs) are common vascular lesions in the brain, affecting approximately 0.5% of the population and representing 10%–20% of all cerebral vascular lesions. One-quarter of all CCMs affect pediatric patients, and CCMs are reported as one of the main causes of brain hemorrhage in this age group. Symptoms include epileptic seizures, headache, and focal neurological deficits. Patients with symptomatic CCMs can be treated either conservatively or with resection if lesions cause medically refractory epilepsy or other persistent symptoms. Methods The authors retrospectively analyzed 79 pediatric patients (41 boys and 38 girls) from 3 different centers, who were surgically treated for their symptomatic CCMs between 1974 and 2004. The mean age of the children at first manifestation was 9.7 years, and the mean age at operation was 11.3 years. The main goal was to compare the clinical outcomes with respect to the location of the lesion of children who preoperatively suffered from epileptic seizures. Results Of these patients, 77.3% were seizure free (Engel Class I) after the resection of the CCM. Significant differences in the outcome between children who harbored CCMs at different locations were not found. Conclusions Resection seems to be the favorable treatment of symptomatic CCMs not only in adults but also in children.

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The pathogenetic features of cerebral cavernous malformations: a comprehensive review with therapeutic implications

Neurosurgical FOCUS ◽

10.3171/2010.6.focus10135 ◽

2010 ◽

Vol 29 (3) ◽

pp. E2 ◽

Cited By ~ 13

Author(s):

Khaled M. Krisht ◽

Kevin J. Whitehead ◽

Toba Niazi ◽

William T. Couldwell

Keyword(s):

Neurological Deficits ◽

Therapeutic Modality ◽

Vascular Lesions ◽

Cerebral Cavernous Malformations ◽

Mice Model ◽

Genetic Studies ◽

Cavernous Malformations ◽

Therapeutic Implications ◽

Model Studies ◽

Shed Light

Cerebral cavernous malformations (CCMs) are common vascular lesions of the CNS that may lead to seizures, focal neurological deficits, and fatal hemorrhagic stroke. Human genetic studies have identified 3 genes associated with CCM, and biochemical and molecular studies in mice have elucidated signaling pathways with important therapeutic implications. In this review, the authors shed light on the 3 discovered CCM genes as well as their protein products, with particular emphasis on their signal transduction pathways and their interaction with one another. Close focus is directed at mice model studies involving the Ccm2 gene product signaling pathway, revealing an important role for the use of simvastatin or other RhoA inhibitors as a therapeutic modality in the treatment of CCM. The remaining challenges to creating a more faithful CCM animal model as well as future clinical and research implications are reviewed.

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