Materiały źródłowe

• #1 Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9105545/

  Cerebral cavernous malformation (CCM) is a cerebromicrovascular disease that affects up to 0.5% of the population. Vessel dilation, decreased endothelial cell-cell contact, and loss of junctional complexes lead to loss of brain endothelial barrier integrity and hemorrhagic lesion formation. […] CCMs are classified as sporadic (sCCM) or familial (fCCM), associated with loss-of-function mutations in KRIT1/CCM1, CCM2, and PDCD10/CCM3. Identifying the CCM proteins has thrust the field forward by (1) revealing cellular processes and signaling pathways underlying fCCM pathogenesis, and (2) facilitating the development of animal models to study CCM protein function. […] Pathogenesis of fCCM is thought to follow the Knudson two-hit hypothesis, where patients are born with one null allele and one functional allele. Although currently unknown, the second hit results in a loss-of-function mutation in the remaining allele, leading to CCM lesion formation.

• #2 Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models

  https://www.mdpi.com/1422-0067/23/9/5000

  Cerebral cavernous malformation (CCM) is a cerebromicrovascular disease that affects up to 0.5% of the population. Vessel dilation, decreased endothelial cell–cell contact, and loss of junctional complexes lead to loss of brain endothelial barrier integrity and hemorrhagic lesion formation. Leakage of hemorrhagic lesions results in patient symptoms and complications, including seizures, epilepsy, focal headaches, and hemorrhagic stroke. CCMs are classified as sporadic (sCCM) or familial (fCCM), associated with loss-of-function mutations in KRIT1/CCM1, CCM2, and PDCD10/CCM3. Identifying the CCM proteins has thrust the field forward by (1) revealing cellular processes and signaling pathways underlying fCCM pathogenesis, and (2) facilitating the development of animal models to study CCM protein function. CCM animal models range from various murine models to zebrafish models, with each model providing unique insights into CCM lesion development and progression. Additionally, these animal models serve as preclinical models to study therapeutic options for CCM treatment. This review briefly summarizes CCM disease pathology and the molecular functions of the CCM proteins, followed by an in-depth discussion of animal models used to study CCM pathogenesis and developing therapeutics.

• #3 Cavernous malformations – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/cavernous-malformations/symptoms-causes/syc-20360941

  Cerebral cavernous malformations (CCMs) are groups of tightly packed, irregular small blood vessels with thin walls. […] Most cerebral cavernous malformations (CCMs) are known as the „sporadic form.” They occur as a single malformation without any family history. […] However, about 20% of people with a CCM have a genetic form. This form is passed down in families, known as familial cavernous malformation syndrome. […] To date, research has identified three genetic changes responsible for cavernous malformations passed down through families. […] Familial CCMs are passed down in families through a change in one of these genes: KRIT1, also called CCM1, CCM2, PDCD10, also called CCM3. […] These genes are responsible for affecting the leakiness of blood vessels and the proteins that keep the blood vessel cells together. […] The most serious complications of cerebral cavernous malformations (CCMs) stem from repeated bleeding, known as hemorrhages. […] Bleeding is more likely to return in people with prior hemorrhages.

• #4 Defining the molecular pathway of Cerebral Cavernous Malformations (CCM) Pathogenesis. | Johnson Lab

  https://www.med.unc.edu/pharm/johnsonlab/research/projects/borikova/

  Cerebral Cavernous Malformations (CCM) are dilated, hyperpermeable microvessels found primarily in the brain. […] Genetic analysis of familial cases has indicated that premature truncations or point mutations within three genes, ccm1, ccm2 or ccm3 are associated with pathogenesis. […] The Johnson lab showed that CCM1, 2 and 3 are scaffold-like adaptor proteins which regulate the stability and activity of the small GTPase RhoA. […] Loss of CCM1, 2 or 3 expression leads to increased RhoA stability and activity, resulting in increased activation of the RhoA effector Rho Kinase (ROCK) and increased phosphorylation of the ROCK target myosin light chain 2 (MLC2). […] The molecular signals which lead to the hyperactivation of RhoA are currently unknown and their identification can lead to potential drug targets for the treatment of CCM. […] My research focuses on defining the molecular mechanism leading to RhoA activation in CCM deficient endothelial cells.

• #5 Baseline and Evolutionary Radiologic Features in Sporadic, Hemorrhagic Brain Cavernous Malformations | American Journal of Neuroradiology

  https://www.ajnr.org/content/early/2019/05/16/ajnr.A6076

  Cavernous malformations (CMs) are angiographically occult vascular malformations that appear in the brain, spinal cord, and rarely nerve roots. Pathologically, they comprise endothelial-lined caverns containing defective tight junctions that predispose these lesions to hemorrhage. […] A typical CM has a reticulated appearance on T2 MR imaging, often likened to mulberries or popcorn. This appearance reflects the underlying pathology in which the caverns may be filled with blood, thrombosis, and calcification. […] However, after an acute hemorrhagic episode, the appearance of a CM is less distinctive and can be difficult to diagnose initially. […] We found that a typical, sporadic, brain hemorrhagic CM decreases in size and evolves to a type II or III lesion if it does not rebleed. Among lesions that did not rebleed, edema resolved within 90 days in all cases.

• #6 Molecular Genetic Features of Cerebral Cavernous Malformations (CCM) Patients: An Overall View from Genes to Endothelial Cells

  https://www.mdpi.com/2073-4409/10/3/704

  Two forms of the disorder have been identified—sporadic (80%) and inherited (20%) disease. Sporadic cases, which occur in people with no family history of CCM, are mostly associated with the presence of a single lesion, while multiple lesions are frequently detected in familial CCM (fCCM). […] The fCCM form has an autosomal dominant inheritance, with incomplete penetrance and variable expressivity. The Knudsonian two-hit mechanism is the most accredited hypothesis to explain CCM pathogenesis. According to this theory, loss of one allele due to a germline mutation in all cells (first hit) is followed by the occurrence, just in some cells, of a somatic mutation in the other allele (second hit), triggering the initiation of the lesions. […] Nevertheless, the definitive cause that determines CCMs remains an open question. In addition to this evidence, another important feature of the CCM condition is the heterogeneity of the phenotypes. More than 350 distinct CCM1/CCM2/CCM3 mutations have been published to date, and patients carrying different mutations in different genes are clinically and phenotypically indistinguishable, although CCM3 patients are often more severely affected with earlier symptomatic onset.

• #7 Genetics of Cavernous Malformation – Alliance to Cure Cavernous Malformation

  https://www.alliancetocure.org/home/cavernous-angioma-in-depth/genetics/genetics-of-cavernous-angioma/

  Mutations of Any of Three Genes Can Cause Familial Cavernous Malformations […] Familial cavernous malformations are caused by a single gene mutation in one of three different genes, CCM1, CCM2, or CCM3. […] Familial cavernous malformations are caused by a hereditary illness that follows an autosomal dominant pattern of inheritance. This means that only one parent must have the illness for it to be passed on to offspring. Each child of a parent with familial cavernous malformation has a 50% chance of inheriting the illness. […] Several studies suggest that lesion formation is seeded when a brain blood vessel cell acquires a second mutation in the other copy of that CCM gene, resulting in a complete loss of function in a brain blood vessel cell. This loss of function causes that cell to start growing and dividing uncontrollably (like a tumor) and starts the formation of a cavernous malformation lesion.

• #8 Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models

  https://www.mdpi.com/1422-0067/23/9/5000

  Pathogenesis of fCCM is thought to follow the Knudson two-hit hypothesis, where patients are born with one null allele and one functional allele. Although currently unknown, the second hit results in a loss-of-function mutation in the remaining allele, leading to CCM lesion formation. Identification of somatic mutations in addition to germline mutations within human CCM lesions validates the two-hit mechanism of pathogenesis. Following loss of the remaining functional allele, CCM-null endothelial cells begin expressing mesenchymal markers and undergo clonal expansion to generate cavernomas. As cavernomas grow, they recruit wild-type endothelial cells, yielding the observed endothelial cell mosaicism in CCM lesions. […] The main hypothesis surrounding CCM lesion progression is that lesion leakage causes patient symptoms and complications, supported by the finding that vascular permeability in the brain and lesions are viable biomarkers for CCM disease progression. Studies conducted with human CCM patients and murine CCM models highlight inflammation as a contributor to CCM progression, with pro-inflammatory cytokine expression and immune cell infiltration of lesions correlating with lesion progression and patient symptoms. Other implicated cell processes contributing to disease progression include increased RhoA kinase activity and PI3K/Akt/mTOR signaling. Ultimately, understanding the cellular processes driving lesion progression is essential to develop therapeutics for CCM lesion stabilization.

• #9 Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9105545/

  Following loss of the remaining functional allele, CCM-null endothelial cells begin expressing mesenchymal markers and undergo clonal expansion to generate cavernomas. […] Because of the described two-hit mechanism of fCCM pathogenesis, sCCM pathogenesis was hypothesized to follow the same two-hit mechanism. This hypothesis was further confirmed through the identification of somatic mutations in CCM genes in sCCM patients. […] Recent studies, however, refute this hypothesis. Only 10% of sCCM lesions contain mutations within CCM genes, and CCM transcript expression is not dysregulated. […] The main hypothesis surrounding CCM lesion progression is that lesion leakage causes patient symptoms and complications, supported by the finding that vascular permeability in the brain and lesions are viable biomarkers for CCM disease progression.

• #10 Endothelial cell clonal expansion in the development of cerebral cavernous malformations | Nature Communications

  https://www.nature.com/articles/s41467-019-10707-x

  Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. […] Here we show that cavernomas originate from clonal expansion of few Ccm3-null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. […] Our findings support the concept that CCMs have benign tumour characteristics and are consistent with the observations of mosaicism in human cavernomas.

• #11 Genetics of Cavernous Malformation – Alliance to Cure Cavernous Malformation

  https://www.alliancetocure.org/home/cavernous-angioma-in-depth/genetics/genetics-of-cavernous-angioma/

  Even though mutations are not inherited in sporadic cavernous malformation, the cause of sporadic lesion development is quite similar to familial lesions. Researchers have found that there are genetic mutations of the CCM genes, but that these mutations occur only in the blood vessels of the sporadic CCM lesion. These mutations are not heritable; they are randomly acquired within brain blood vessels and cause a CCM lesion to form. […] This data suggests that all forms of CCM lesions develop following a similar mechanism (a complete loss of function of one of the CCM genes within the brain blood vessel cells). Because of this biological similarity, there is optimism that the same therapeutic drug may treat all forms of CCM in the future. […] Research has uncovered that these three gene products (proteins) each have their own unique properties, and also work together as part of a signaling complex, communicating and interacting with each other. The signaling complex is related to critical processes, such as maintaining the tight junctions between neighboring blood vessel cells, cell cycle regulation, and blood vessel development.

• #12 Genetics of Cavernous Malformation – Alliance to Cure Cavernous Malformation

  https://www.alliancetocure.org/genetics/genetics-of-cavernous-angioma/

  Even though mutations are not inherited in sporadic cavernous malformation, the cause of sporadic lesion development is quite similar to familial lesions. Researchers have found that there are genetic mutations of the CCM genes, but that these mutations occur only in the blood vessels of the sporadic CCM lesion. […] This data suggests that all forms of CCM lesions develop following a similar mechanism (a complete loss of function of one of the CCM genes within the brain blood vessel cells). […] Research has uncovered that these three gene products (proteins) each have their own unique properties, and also work together as part of a signaling complex, communicating and interacting with each other. The signaling complex is related to critical processes, such as maintaining the tight junctions between neighboring blood vessel cells, cell cycle regulation, and blood vessel development. […] A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2, or CCM3 in affected endothelial cells.

• #13 Investigating The Role Of Pi3k Signaling In Cerebral Cavernous Malformation Pathogenesis

  https://repository.upenn.edu/items/50fddcb4-b229-4f5e-bde7-d470c3ae8e1f

  Cerebral cavernous malformations (CCMs), or cavernomas, are abnormal vascular growths that arise in the central nervous system and have no approved medical treatment. […] Our study reveals a synergistic interaction that underlies a significant proportion of aggressive human CCMs and answers this long-standing question in the field. […] Using mouse genetic models, we show that cavernoma growth requires two distinct inputs, one through loss of the CCM protein complex as previously described, and another through gain of PI3K signaling, which can be provided either by endogenous angiogenic signals in the neonatal mouse model or by activating mutations in PIK3CA commonly found in cancer. […] We identify somatic mutations in PIK3CA in 71% of resected human cavernomas and via single-nucleus DNA sequencing, reveal that PIK3CA mutations arise in the same cells as CCM gene mutations.

• #14 Investigating The Role Of Pi3k Signaling In Cerebral Cavernous Malformation Pathogenesis

  https://repository.upenn.edu/items/50fddcb4-b229-4f5e-bde7-d470c3ae8e1f

  Our study establishes a “three-hit” mechanism analogous to cancer in which aggressive vascular malformations arise through the loss of vascular “suppressor genes” required to constrain vessel growth and gain of a vascular “oncogene” that stimulates excess vessel growth. […] To our knowledge, this is the first description of a compound genetic mechanism in vascular malformation pathogenesis. […] Consistent with these findings, the mTORC1 inhibitor Rapamycin effectively blocks CCM formation in both neonatal and adult mouse models.

• #15 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20210428/Mutation-in-a-cancer-causing-gene-could-exacerbate-cerebral-cavernous-malformations-in-the-brain.aspx

  Researchers have discovered an explanation for why cerebral cavernous malformations (CCMs)–clusters of dilated blood vessels in the brain–can suddenly grow to cause seizures or stroke. Specifically, they found that a specific, acquired mutation in a cancer-causing gene (PIK3CA) could exacerbate existing CCMs in the brain. […] Using mouse genetic models of CCM formation, the researchers discovered that it is the additional „hit” that stimulates the known cancer-causing gene PIK3CA and leads to the rapid growth of existing CCMs. When they examined resected human CCM tissue, they saw the same genes were involved, which supports the idea of a „cancer-like” mechanism for accelerated blood vessel malformation growth in which small quiescent CCMs become „malignant” after a new gene mutation occurs.

• #16 Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg2011155

  Second, haploinsufficiency may also be an explanation in CCM pathophysiology. In this case, the patient has only a single functional copy of one of the CCM genes, due to mutational inactivation of the other. The single functional copy of the gene, however, does not result in sufficient protein for, for example, an adequate functional junction formation between endothelial cells, which in turn leads to the development of abnormal vascular structures. […] Finally, trans-heterozygosity, in which a patient has synergistic mutations in different genes of the CCM pathway (for example, a germline mutation in the KRIT1 gene with an additional somatic mutation in the MGC4607 or PDCD10 gene), might also explain intrafamilial clinical variability. Indeed, it has been shown that a decrease in the KRIT1, MGC4607 or PDCD10 gene alone caused little or no effect independently, but when combined, resulted in very high incidence of intracranial haemorrhage.

• #17 Molecular Genetic Features of Cerebral Cavernous Malformations (CCM) Patients: An Overall View from Genes to Endothelial Cells

  https://www.mdpi.com/2073-4409/10/3/704

  All of the three discovered genes associated with CCMs found in mammals, vertebrates, and simple organisms (i.e., Caenorhabditis elegans), are well conserved among species, giving the advantage of exploiting numerous animal models to progress in the knowledge of this pathological condition. […] The inherited nature of CCM and the discovery of disease-related genes sparked interest in investigating their functional roles. The ubiquitous expression of the three CCM genes in various cells and tissues provides evidence for their contribution in several physiological and pathological conditions. However, the cellular type most strongly associated with cavernous malformations is the endothelial cell. […] Each gene product is a multi-domain adaptor protein, which interacts with numerous binding molecules and participates in several different signaling pathways. On the other hand, KRIT1, CCM2, and PDCD10 proteins can exist into a heterotrimeric complex, the CCM signaling complex (CSC), being partners in numerous cellular processes that significantly affect CCM development and pathogenesis. Thus, CCM proteins fulfill critical roles in many cellular events, such as cell polarity, cytoskeletal reorganization, cell proliferation, cellular adhesion, and migration, impacting angiogenesis, cell–cell junction integrity, vascular permeability, and apoptosis, whether as part of the ternary complex or not.

• #18 INTRODUCTION

  http://koreascience.or.kr/article/JAKO201619039485168.page

  The disease known as cerebral cavernous malformations mostly occurs in the central nervous system, and their typical histological presentations are multiple lumen formation and vascular leakage at the brain capillary level, resulting in disruption of the blood-brain barrier. […] CCM research has identified 'loss of function’ mutations of three ccm genes responsible for the disease and also complex regulation of multiple signaling pathways including the WNT/-catenin pathway, TGF- and Notch signaling by the ccm genes. […] Pathogenesis of CCM follows the Knudsonian two-hit mechanism, in which loss of one allele due to a germline mutation of one of the three known CCM genes in an affected cell (first hit) is accompanied with somatic mutation in the other (second hit). […] Activation of RhoA and its effector, Rho kinase (ROCK), induces stress fiber formation, resultant decreased stability of adherens junction and abnormal extracellular matrix (ECM) remodeling, and increases endothelial permeability.

• #19 Molecular Pathogenesis of Cerebral Cavernous Malformations | PPT

  https://www.slideshare.net/slideshow/molecular-pathogenesis-of-cerebral-cavernous-malformations/62088337

  The leaky vasculature in CCM lesions is explained by their weak and disordered cell-cell junctions. […] The first indication that RhoA dysregulation might contribute to CCM pathology came from the observation of increased stress fiber formation (a sign of activated RhoA) after knockdown of any of the CCM proteins. […] In animal models, CCM1/KRIT1, CCM2 and CCM3/PDCD10 are essential for cardiovascular development. Loss of either KRIT1 or CCM3/PDCD10 leads to an induction of angiogenesis by impaired DeltaNotch signaling, and CCM3/PDCD10 might be essential for venous endothelial cell differentiation. […] Fasudil, a Rho kinase inhibitor, is able to reduce development and hemorrhagic rates of CCM lesions in a mouse model of CCM-1 disease compared with placebo controls. […] Statin drugs may be used for treating CCM through the inhibition of Rho GTPases. There is evidence that the Rho GTPase pathway can be directly activated by ROS. […] Sorafenib can ameliorate loss of CCM1-induced excessive microvascular growth, by reducing the microvessel density to levels of normal wild-type endothelial cells; in this way, it could be a potential therapeutic approach also for humans.

• #20 The Molecular Pathogenesis Of Cerebral Cavernous Malformations

  https://repository.upenn.edu/items/cba5ee64-24a0-4865-8389-c58e06b9f9ec

  Cerebral cavernous malformation (CCM) is a human genetic, cerebrovascular disease that is caused by loss of function mutations in three non-homologous protein coding genes: KRIT1, CCM2, and PDCD10. […] Here, utilizing a neonatal mouse model of disease, we demonstrate that the CCM complex negatively regulates Mitogen-Activated Protein Kinase Kinase Kinase 3 (MAP3K3 aka MEKK3) signaling in endothelial cells. […] During disease, loss of the CCM complex results in gain of MEKK3 signaling and pathologic overexpression of downstream target transcription factors Kruppel-like Factor 2 and Kruppel-like factor 4 (KLF2 and KLF4). […] This endothelial MEKK3-KLF2/4 signaling pathway represents the proximal signaling events that are required for lesion formation. […] We demonstrate that gram-negative bacterial infection and lipopolysaccharide (LPS) activation of endothelial Toll-like receptor 4 (TLR4) drives MEKK3 signaling to stimulate lesion formation.

• #21 Cerebral cavernous malformation pathogenesis [Neurosurgery Education Wiki]

  https://neurosurgery.education/wiki/doku.php?id=cerebral_cavernous_malformation_pathogenesis

  Significant research findings from 2000 to 2015 have further enhanced our understanding of the pathogenesis of CCM formation. […] Studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics. […] CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. […] These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment.

• #22 Molecular Pathogenesis of Cerebral Cavernous Malformations | PPT

  https://www.slideshare.net/slideshow/molecular-pathogenesis-of-cerebral-cavernous-malformations/62088337

  Loss of CCM1/KRIT1 also reduces the expression of the reactive oxygen species (ROS)-scavenging enzyme superoxide dismutase SOD2 with consequent increases in the steady state levels of ROS and AKT phosphorylation. […] Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal- and stem-cell- like characteristics by the endothelium. Endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. […] CCM1/KRIT1 is thought to harbor intramolecular binding sites, i.e. its N-terminus can interact with its FERM domain. […] All three CCM genes are important in endothelial cell biology and vascular development. However, not all CCM gene products seem to perform the same functions.

• #23 Central nervous system cavernous hemangioma – Wikipedia

  https://en.wikipedia.org/wiki/Central_nervous_system_cavernous_hemangioma

  Cerebral cavernous malformation (CCM) is a cavernous hemangioma that arises in the central nervous system. It can be considered to be a variant of hemangioma, and is characterized by grossly large dilated blood vessels and large vascular channels, less well circumscribed, and more involved with deep structures, with a single layer of endothelium and an absence of neuronal tissue within the lesions. These thinly walled vessels resemble sinusoidal cavities filled with stagnant blood. Blood vessels in patients with cerebral cavernous malformations (CCM) can range from a few millimeters to several centimeters in diameter. Most lesions occur in the brain, but any organ may be involved. […] Many molecular mechanisms have been identified in CCM pathology. In 2015 it was reported that the endothelial cells forming cerebral vascular malformations undergo an endothelial to mesenchymal transition in both sporadic and familial CCM. […] CCM mutant endothelial cells have been reported to undergo clonal expansion and be able to recruit non-mutant cells into the lesions. Recently, immunothrombosis and hypoxia have also been reported to be dysregulated in CCM.

• #24

  https://www.omim.org/entry/116860

  For each of the 3 CCM genes, Pagenstecher et al. (2009) showed complete localized loss of either KRIT1 (604214), CCM2/malcavernin, or PDCD10 (609118) protein expression depending on the respective inherited mutation. […] Pagenstecher et al. (2009) suggested that complete lack of CCM protein in affected endothelial cells from CCM germline mutation carriers supports a 2-hit mechanism for CCM formation. […] Maddaluno et al. (2013) demonstrated that endothelial-specific disruption of the KRIT1 gene in mice induces endothelial-to-mesenchymal transition, which contributes to the development of vascular malformations. […] Thus, increased TGF-beta and BMP signaling, and the consequent endothelial-to-mesenchymal transition of KRIT1-null endothelial cells, are crucial events in the onset and progression of cerebral cavernous malformation disease.

• #25 INTRODUCTION

  https://www.koreascience.or.kr/article/JAKO201619039485168.page

  Activation of RhoA and its effector, Rho kinase (ROCK), induces stress fiber formation, resultant decreased stability of adherens junction and abnormal extracellular matrix (ECM) remodeling, and increases endothelial permeability. […] Recent studies elegantly demonstrated endothelial-mesenchymal transition (EndMT) in endothelial cells lining CCMs in tamoxifen-inducible CCM1 loss of function mice. […] EndMT may occur as a result of upregulation of endogenous bone morphogenetic protein 6 (BMP6) and activation of the transforming growth factor (TGF)- and bone morphogenetic protein (BMP) signaling pathways. […] Autophagy appears to be another important mechanism of CCM pathogenesis because ablation of ccm1, ccm2 and ccm3 commonly causes mTOR-ULK1 pathway mediated suppression of autophagy and resultant EndMT.

• #26 INTRODUCTION

  http://koreascience.or.kr/article/JAKO201619039485168.page

  Recent studies elegantly demonstrated endothelial-mesenchymal transition (EndMT) in endothelial cells lining CCMs in tamoxifen-inducible CCM1 loss of function mice. […] Autophagy appears to be another important mechanism of CCM pathogenesis because ablation of ccm1, ccm2 and ccm3 commonly causes mTOR-ULK1 pathway mediated suppression of autophagy and resultant EndMT. […] Combinational effects and genetic modifiers may explain radiological and clinical incomplete penetrance of CCM. […] Because functional manipulation of CCM signaling has a good potential for regulating systemic blood vessel permeability and angiogenesis, the research field of CCM is now growing rapidly.

• #27 Recent advances in cerebral cavernous malformation research

  https://www.oaepublish.com/articles/2574-1209.2018.34

  Homozygous mutations in any of the three CCM proteins are nonviable, indicating their essential role in biogenesis as phenotype suppressors. […] CCM1 is a regulator of FoxO1, through an unknown mechanism. This transcription factor induces the transcription of Sod2 and Sirt1, two important anti-oxidants in the cell. […] CCM1 provides protection against oxidative stress in the cell by utilizing anti-inflammatory and anti-oxidant pathways. […] CCM lesions show defect in autophagy through increased activity of mTOR. Inhibitors of mTOR were shown to reverse the defect in autophagy suggesting that mTOR is involved in the process, which provides another set of pharmacotherapeutic agents in CCM.

• #28 Cerebral cavernous malformation pathogenesis [Neurosurgery Education Wiki]

  https://neurosurgery.education/wiki/doku.php?id=cerebral_cavernous_malformation_pathogenesis

  CCMs arise due to loss of function in one of the genes that encode the CCM complex, a negative regulator of MEKK3-KLF2/4 signaling in vascular endothelial cells. […] Gain-of-function mutations in PIK3CA (encoding the enzymatic subunit of the PI3K (phosphoinositide 3-kinase) pathway associated with cell growth) synergize with CCM gene loss-of-function to generate rapidly growing lesions. […] Ren et al. demonstrated that CCM growth requires increased PI3K/AKT/mTOR pathway and loss of CCM protein function. […] They established a three-hit mechanism analogous to cancer in which aggressive vascular malformations arise through the loss of vascular suppressor genes that constrain vessel growth and gain of a vascular oncogene that stimulates excess vessel growth. […] How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/-catenin) and processes such as endothelial mesenchymal transition (EndMT) proposed to have causal roles.

• #29 Endothelial cell clonal expansion in the development of cerebral cavernous malformations | Nature Communications

  https://www.nature.com/articles/s41467-019-10707-x

  We have shown that cavernomas originate from clonal expansion of Ccm3-null endothelial cells that co-express endothelial and mesenchymal/stem cell markers and trigger the recruitment of Ccm3+/+ endothelial cells. […] These data thus support the idea that endothelial progenitors are responsible for the triggering of cavernoma formation upon Ccm3 deletion.

• #30 Investigating the Pathogenesis and Response to Therapy of Cerebral Cavernous Malformations Using Transgenic Murine Models

  https://dukespace.lib.duke.edu/items/c61ac8eb-c588-43df-b786-000faa913691

  Cerebral cavernous malformations (CCMs), also known as cavernous angiomas, are clusters of sinusoidal capillary-venous vessels that develop in the approximately 1 in 200 individuals. […] CCMs develop following biallelic loss-of-function mutations in CCM1, CCM2, or CCM3. […] How a single mutant endothelial cell leads to the formation of large, multicellular malformation is not known. […] We discovered that mutant endothelial cells undergo clonal expansion and incorporate wild-type endothelial cells as the malformation grows. […] These new insights and transgenic tools further our understanding of this disease and advance the research communitys efforts to identify a medical treatment for CCMs.

• #31

  https://www.omim.org/entry/116860

  Using a neonatal mouse model of CCM disease, Zhou et al. (2016) showed that expression of the MEKK3 (602539) target genes Klf2 (602016) and Klf4 (602253), as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. […] The authors concluded that their studies identified gain of MEKK3 signaling and KLF2/4 function as causal mechanisms for CCM pathogenesis. […] Tang et al. (2017) identified TLR4 (603030) and the gut microbiome as critical stimulants of CCM formation. […] Tang et al. (2017) concluded that their studies identified unexpected roles for the microbiome and innate immune signaling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment.

• #32 A new mechanism identifies a gut-brain axis in cerebral cavernous malformation

  https://www.gutmicrobiotaforhealth.com/a-new-mechanism-identifies-a-gut-brain-axis-in-cerebral-cavernous-malformation/

  A new publication from Alan T. Tang of the University of Pennsylvania focuses on explaining the relationship between gut microbiota and cerebral cavernous malformation (CCM), which is a neurological disease that leads to hemorrhagic stroke and seizure. […] The disease mainly occurs due to genetic variation with heterozygous loss-of-function mutations in the KRIT1, CCM2 and PDCD10 genes, which encode components of an adaptor protein complex. […] Recent studies have shown that the lipopolysaccharide (LPS), presented by gram-negative bacteria in the gut microbiota, activate Toll-like receptor 4 (TLR4) in the brain. […] To identify PDCD10’s role, they first compared the gut microbiota composition of 75 genotyped CCM patients from the United States with that of 29 healthy volunteers. […] Indeed, only PDCD10 deletion led to an increase in colonic epithelium lesions, characterized by reduction of mucus layer, crypt dilation and abscesses and presence of Ly6G positive neutrophils.

• #33 The Molecular Pathogenesis Of Cerebral Cavernous Malformations

  https://repository.upenn.edu/items/cba5ee64-24a0-4865-8389-c58e06b9f9ec

  These studies reveal that endothelial TLR4—MEKK3—KLF2/4 signaling is required for lesion formation and that inhibition of this pathway may be of therapeutic value for CCM patients. […] They further demonstrate an unexpected role for the gut microbiome in this cerebrovascular disease and suggest that manipulation of host-microbiome interactions may be a viable therapeutic strategy for this lifelong, progressive disease.

• #34 Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9105545/

  Studies conducted with human CCM patients and murine CCM models highlight inflammation as a contributor to CCM progression, with pro-inflammatory cytokine expression and immune cell infiltration of lesions correlating with lesion progression and patient symptoms. […] Ultimately, understanding the cellular processes driving lesion progression is essential to develop therapeutics for CCM lesion stabilization.

• #35

  https://www.jci.org/articles/view/44393

  These findings suggest that PDCD10 influences different endothelial signaling pathways from KRIT1/CCM2 to lead to a common histopathology and imply that medical treatment to stabilize familial CCM may need to be developed and evaluated in a genotype-specific manner. […] Loss of PDCD10 does not affect RhoA signaling but results in lumen formation defects. […] Thus, the role of PDCD10 in endothelial cell biology and signaling differs from that of CCM2. […] Our data support the model that PDCD10 signals through the GCKIII family kinases, as we have observed in human endothelial cells and in Drosophila that PDCD10 binds to GCKIII family kinases and both are required for lumen formation. […] Using an inducible Cre-recombinase, we have targeted gene-specific LOH for both Pdcd10 and Ccm2 to the endothelium of mice. […] In the case of both genes, we have found that LOH is sufficient to cause a fully penetrant CCM phenotype that recapitulates every key pathologic and radiologic hallmark of human disease.

• #36 Propranolol therapy for cerebral cavernous malformations

  https://www.spandidos-publications.com/10.3892/wasj.2022.158

  Cerebral cavernous malformations (CCMs) are vascular malformations characterized by the abnormal growth of vascular structures in the central nervous system. However, the precise mechanism(s) responsible for the development of CCM vascular abnormalities remain poorly understood. […] The exact mechanisms that regulate the development of vascular abnormalities remain poorly understood. It is known that during the growth phase of hemangiomas, the increased expression of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) is associated with ECs and interstitial cell proliferation. […] The exact mechanisms through which propranolol interferes with angiogenesis are not yet known; however, some studies have indicated that its anti-angiogenic effects are mediated by the downregulation of VEGF and FGF levels. […] Propranolol, apart from promoting the regression of CCM, impairs CD14+/CD31+ cell circulation, in part by the decreased VEGF levels. […] The underlying mechanism may involve the control of monocyte differentiation into ECs and how these cells are phenotypically altered.

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