scholarly journals Mural Cell-Specific Deletion of Cerebral Cavernous Malformation 3 in the Brain Induces Cerebral Cavernous Malformations

2020 ◽  
Vol 40 (9) ◽  
pp. 2171-2186
Author(s):  
Kang Wang ◽  
Haifeng Zhang ◽  
Yun He ◽  
Quan Jiang ◽  
Yoshiaki Tanaka ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Adhesion Formation ◽  
Single Layer ◽  
Cerebral Cavernous Malformations ◽  
Mural Cell ◽  
Cavernous Malformations ◽  
Mural Cells ◽  
Brain Pericytes ◽  
The Brain ◽  
Specific Deletion

Objective: Cerebral cavernous malformations (CCM), consisting of dilated capillary channels formed by a single layer of endothelial cells lacking surrounding mural cells. It is unclear why CCM lesions are primarily confined to brain vasculature, although the 3 CCM-associated genes ( CCM1 , CCM2 , and CCM3 ) are ubiquitously expressed in all tissues. We aimed to determine the role of CCM gene in brain mural cell in CCM pathogenesis. Approach and Results: SM22α -Cre was used to drive a specific deletion of Ccm3 in mural cells, including pericytes and smooth muscle cells (Ccm3smKO). Ccm3smKO mice developed CCM lesions in the brain with onset at neonatal stages. One-third of Ccm3smKO mice survived upto 6 weeks of age, exhibiting seizures, and severe brain hemorrhage. The early CCM lesions in Ccm3smKO neonates were loosely wrapped by mural cells, and adult Ccm3smKO mice had clustered and enlarged capillary channels (caverns) formed by a single layer of endothelium lacking mural cell coverage. Importantly, CCM lesions throughout the entire brain in Ccm3smKO mice, which more accurately mimicked human disease than the current endothelial cell-specific CCM3 deletion models. Mechanistically, CCM3 loss in brain pericytes dramatically increased paxillin stability and focal adhesion formation, enhancing ITG-β1 (integrin β1) activity and extracellular matrix adhesion but reducing cell migration and endothelial cell-pericyte associations. Moreover, CCM3-wild type, but not a paxillin-binding defective mutant, rescued the phenotypes in CCM3-deficient pericytes. Conclusions: Our data demonstrate for the first time that deletion of a CCM gene in the brain mural cell induces CCM pathogenesis.

Integrative analysis of the human brain mural cell transcriptome

2021 ◽  
pp. 0271678X2110137
Author(s):  
Benjamin D Gastfriend ◽  
Koji L Foreman ◽  
Moriah E Katt ◽  
Sean P Palecek ◽  
Eric V Shusta
Keyword(s):  
Human Brain ◽  
Cell Function ◽  
In Vitro Models ◽  
Molecular Characteristics ◽  
Mural Cell ◽  
Mural Cells ◽  
Brain Pericytes ◽  
Mouse Species ◽  
Cell Transcriptome

Brain mural cells, including pericytes and vascular smooth muscle cells, are important for vascular development, blood-brain barrier function, and neurovascular coupling, but the molecular characteristics of human brain mural cells are incompletely characterized. Single cell RNA-sequencing (scRNA-seq) is increasingly being applied to assess cellular diversity in the human brain, but the scarcity of mural cells in whole brain samples has limited their molecular profiling. Here, we leverage the combined power of multiple independent human brain scRNA-seq datasets to build a transcriptomic database of human brain mural cells. We use this combined dataset to determine human-mouse species differences in mural cell transcriptomes, culture-induced dedifferentiation of human brain pericytes, and human mural cell organotypicity, with several key findings validated by RNA fluorescence in situ hybridization. Together, this work improves knowledge regarding the molecular constituents of human brain mural cells, serves as a resource for hypothesis generation in understanding brain mural cell function, and will facilitate comparative evaluation of animal and in vitro models.

Aeromedical Implications of Cerebral Cavernomas

2021 ◽  
Vol 92 (2) ◽  
pp. 120-123
Author(s):  
Tania Jagathesan ◽  
Michael OBrien
Keyword(s):  
Clinical Presentation ◽  
Clinical Symptoms ◽  
Civil Aviation ◽  
Complication Rates ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Medical Certification ◽  
The Uk ◽  
Age Range ◽  
The Brain

BACKGROUND: Cavernomas, cavernous angiomas, or cerebral cavernous malformations are clusters of endothelium-lined blood vessels usually found in the brain. With the increasing use of radiological imaging, these are being detected incidentally in asymptomatic aircrew. The UK Civil Aviation Authority (CAA) experience of cavernomas is described and the aeromedical concerns, that is, the risk of epilepsy, hemorrhage, and the development of a neurological deficit, are considered.METHODS: A search of the CAA database between 1990 and 2020 was performed for the term cavernoma. The gender, age at diagnosis, class of certification held, clinical presentation, location, and size of the lesion were noted. A PubMed literature review for papers with complications of cavernoma was performed.RESULTS: Six cases of cavernoma have been declared to the CAA: five professional pilots and one private pilot. Five were men and one was a woman. The age range was between 38 and 60 yr, with a mean of 48 yr. Two cases presented with clinical symptoms and four were asymptomatic. Complication rates for seizure and hemorrhage were extracted from the published literature together with the significance of other factors such as cavernoma size, family history, multiplicity, and the development of new lesions.DISCUSSION: A policy for the medical certification of aircrew with cavernomas that have presented with clinical symptoms and those that are detected incidentally is proposed.Jagathesan T, OBrien M. Aeromedical implications of cerebral cavernomas. Aerosp Med Hum Perform. 2021; 92(2):120123.

scholarly journals Endothelial cell clonal expansion in the development of cerebral cavernous malformations

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Matteo Malinverno ◽  
Claudio Maderna ◽  
Abdallah Abu Taha ◽  
Monica Corada ◽  
Fabrizio Orsenigo ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Clonal Expansion ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Cell Clonal Expansion

The Neurovascular Unit: Focus on the Regulation of Arterial Smooth Muscle Cells

2020 ◽  
Vol 16 (5) ◽  
pp. 502-515 ◽  
Author(s):  
Patrícia Quelhas ◽  
Graça Baltazar ◽  
Elisa Cairrao
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Blood Vessels ◽  
Neurovascular Unit ◽  
Muscle Cells ◽  
Cerebral Blood Vessels ◽  
Mural Cells ◽  
Brain Pericytes ◽  
The Brain

The neurovascular unit is a physiological unit present in the brain, which is constituted by elements of the nervous system (neurons and astrocytes) and the vascular system (endothelial and mural cells). This unit is responsible for the homeostasis and regulation of cerebral blood flow. There are two major types of mural cells in the brain, pericytes and smooth muscle cells. At the arterial level, smooth muscle cells are the main components that wrap around the outside of cerebral blood vessels and the major contributors to basal tone maintenance, blood pressure and blood flow distribution. They present several mechanisms by which they regulate both vasodilation and vasoconstriction of cerebral blood vessels and their regulation becomes even more important in situations of injury or pathology. In this review, we discuss the main regulatory mechanisms of brain smooth muscle cells and their contributions to the correct brain homeostasis.

Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis

2013 ◽  
Vol 19 (5) ◽  
pp. 302-308 ◽  
Author(s):  
Andreas Fischer ◽  
Juan Zalvide ◽  
Eva Faurobert ◽  
Corinne Albiges-Rizo ◽  
Elisabeth Tournier-Lasserve
Keyword(s):  
Endothelial Cell ◽  
Cerebral Cavernous Malformations ◽  
Cell Homeostasis ◽  
Cavernous Malformations

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

2011 ◽  
Vol 8 (5) ◽  
pp. 522-525 ◽  
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.

scholarly journals Conserved and context-dependent roles for Pdgfrb signaling during zebrafish vascular mural cell development

2021 ◽  
Author(s):  
Koji Ando ◽  
Yu-Huan Shih ◽  
Lwaki Ebarasi ◽  
Ann Grosse ◽  
Daneal Portman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Coronary Vessels ◽  
Structural Defects ◽  
Mural Cell ◽  
Larval Stages ◽  
Mural Cells ◽  
Brain Pericytes ◽  
Juvenile Stages ◽  
Mutant Lines

Platelet derived growth factor beta and its receptor, Pdgfrb, play essential roles in the development of vascular mural cells, including pericytes and vascular smooth muscle. To determine if this role was conserved in zebrafish, we analyzed pdgfb and pdgfrb mutant lines. Similar to mouse, pdgfb and pdgfrb mutant zebrafish lack brain pericytes and exhibit anatomically selective loss of vascular smooth muscle coverage. Despite these defects, pdgfrb mutant zebrafish did not otherwise exhibit circulatory defects at larval stages. However, beginning at juvenile stages, we observed severe cranial hemorrhage and vessel dilation associated with loss of pericytes and vascular smooth muscle cells in pdgfrb mutants. Similar to mouse, pdgfrb mutant zebrafish also displayed structural defects in the glomerulus, but normal development of hepatic stellate cells. We also noted defective mural cell investment on coronary vessels with concomitant defects in their development. Together, our studies support a conserved requirement for Pdgfrb signaling in mural cells. In addition, these mutants provide an important model for definitive investigation of mural cells during early embryonic stages without confounding secondary effects from circulatory defects.

scholarly journals Genetic Genealogy Uncovers a Founder Deletion Mutation in the Cerebral Cavernous Malformations 2 Gene

2021 ◽  
Author(s):  
Carol J Gallione ◽  
Matthew R Detter ◽  
Henrietta M Christmas ◽  
Cornelia Lee ◽  
Douglas A Marchuk
Keyword(s):  
Vascular Malformations ◽  
Cerebral Cavernous Malformations ◽  
Autosomal Dominant Trait ◽  
Cavernous Malformations ◽  
North American Continent ◽  
The North ◽  
Genealogical Data ◽  
The Brain ◽  
Recombination Junction ◽  
Pair Level

Abstract Cerebral cavernous malformations (CCM) are vascular malformations consisting of collections of enlarged capillaries occurring in the brain or spinal cord. These vascular malformations can occur sporadically or susceptibility to develop these can be inherited as an autosomal dominant trait due to mutation in one of three genes. Over a decade ago, we described a 77.6 Kb germline deletion spanning exons 2-10 in the CCM2 gene found in multiple affected individuals from seemingly unrelated families. Segregation analysis using linked, microsatellite markers indicated that this deletion may have arisen at least twice independently. In the ensuing decades, many more CCM patients have been identified with this deletion. In this present study we examined 27 reportedly unrelated affected individuals with this deletion. To investigate the origin of the deletion at base pair level resolution, we sequenced approximately 10 Kb upstream and downstream from the recombination junction on the deleted allele. All patients showed the identical SNP haplotype across this combined 20 Kb interval. In parallel, genealogical records have traced 11 of these individuals to five separate pedigrees dating as far back as the 1600-1700’s. These haplotype and genealogical data suggest that these families and the remaining “unrelated” samples converge on a common ancestor due to a founder mutation occurring centuries ago on the North American continent. We also note that another gene, NACAD, is included in this deletion. Although patient self-reporting does not indicate an apparent phenotypic consequence for heterozygous deletion of NACAD, further investigation is warranted for these patients.

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