scholarly journals CCM2L (Cerebral Cavernous Malformation 2 Like) Deletion Aggravates Cerebral Cavernous Malformation Through Map3k3-KLF Signaling Pathway

Stroke ◽  
2021 ◽  
Vol 52 (4) ◽  
pp. 1428-1436
Author(s):  
Jaesung P. Choi ◽  
Xi Yang ◽  
Shuang He ◽  
Renhua Song ◽  
Zi-Ran Xu ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Signaling Pathway ◽  
Cavernous Malformation ◽  
Cerebral Cavernous Malformation ◽  
Neurological Deficits ◽  
Lesion Volume ◽  
Compensatory Mechanism ◽  
Micro Computed Tomography ◽  
Deficient Mice

Background and Purpose: Cerebral cavernous malformation (CCM) is a common cerebrovascular disease. CCMs are major causes of stroke, cerebral hemorrhage, and neurological deficits in young individuals. Loss-of-function mutations in CCM1 , CCM2 , and CCM3 have been identified to cause CCM in humans. Ccm2-like ( Ccm2l ) is a paralog of Ccm2 and is predominantly expressed in endothelial cells (ECs). CCM2L (CCM2-like) competes with CCM2 for binding to CCM1 and has been shown to have an antagonistic function to that of CCM2 during vascular development. The role of CCM2L in CCM pathogenesis is unknown. Methods: We isolated brain ECs from the inducible-CCM mouse models for gene expression analysis. Micro-computed tomography imaging was used to analyze CCM lesion burden from the genetic cross of Ccm2l knockout mice ( Ccm2l −/− ) with Ccm1 or Ccm2 -deficient mice to determine the role of Ccm2l in CCM pathogenesis. Genetic crosses with Map3k3 fl/fl mice were used to determine the role of Map3k3 in Ccm2l -facilitated CCM formation. Results: We demonstrated increased Ccm2l expression in brain ECs of Ccm2 -deficient mice. Analysis of RNA-seq data from CCM patient samples revealed a trend of increased CCM2L expression and its positive correlation with Kruppel-like factor 2/4 (KLF2/4 ) expression. Micro-computed tomography revealed that the deletion of Ccm2l in Ccm2 -deficient mice increased CCM lesion volume compared with that of controls but had no effect on lesion numbers. Correlating to the increased lesion burden, Klf2/4 mRNA expressions in brain ECs were significantly increased in double knockouts ( Ccm2 - and Ccm2l -deficient mice) compared with that of controls ( Ccm2 deficient). Hemizygous deletion of Map3k3 in ECs relieved CCM lesion burden in the double knockouts. These results suggest that CCM2L regulates the Map3k3-KLF signaling pathway in CCM pathogenesis. Conclusions: Loss of CCM2L aggravates CCM lesion formation in the Ccm2 -deficient mouse model through increased Map3k3-KLF signaling. Our data suggest that increased Ccm2l expression is a compensatory mechanism in CCM pathogenesis.

Stereotactic radiosurgery for cerebral cavernous malformation: comparison of hemorrhage rates before and after stereotactic radiosurgery

2021 ◽  
pp. 1-7
Author(s):  
Burak Karaaslan ◽  
Beste Gülsuna ◽  
Gökberk Erol ◽  
Özlem Dağli ◽  
Hakan Emmez ◽  
...  
Keyword(s):  
Stereotactic Radiosurgery ◽  
Seizure Control ◽  
Cavernous Malformation ◽  
Cerebral Cavernous Malformation ◽  
Vascular Pathology ◽  
Lesion Volume ◽  
Developmental Venous Anomaly ◽  
Effective Treatment Modality ◽  
Radiological Data ◽  
Before And After

OBJECTIVE Cerebral cavernous malformation (CM) is an angiographically occult vascular pathology. Although microsurgery is the gold standard treatment to control the symptoms of CM, resection carries high risk in some situations, especially eloquent areas. The objective was to evaluate annual hemorrhage rates (AHRs) before and after stereotactic radiosurgery (SRS) treatment of cerebral CM in different locations. METHODS A total of 195 patients (119 women and 76 men) with CM treated at the Gazi University Gamma Knife Center between April 2005 and June 2017 were analyzed. The mean ± SD follow-up period was 67.4 ± 31.1 months (range 12 days to 170 months). AHR before SRS, AHR after SRS, morbidity associated with radiation, seizure control rate after SRS, lesion volume, coexistence with developmental venous anomaly, and SRS treatment parameters were analyzed, with evaluation of radiological data and clinical charts performed retrospectively. The seizure control rate was assessed using the Engel outcome scale. RESULTS The AHR before SRS was 15.3%. Application of SRS to these patients significantly reduced the AHR rates to 2.6% during the first 2 years after treatment and to 1.4% thereafter. Favorable seizure control (Engel class I and II) after radiosurgery was achieved in 23 patients (88.5%) with epilepsy. Radiation-related temporary complications occurred in 15.4% of patients, and permanent morbidity occurred in 4.6%. CONCLUSIONS SRS is a safe and effective treatment modality for reducing the hemorrhage risk of CM. The authors suggest that SRS should be considered for the treatment of patients with CM, high surgical risks, and hemorrhage history, instead of a using a wait-and-see policy.

scholarly journals Role of cytoskeletal proteins in cerebral cavernous malformation signaling pathways: a proteomic analysis

2014 ◽  
Vol 10 (7) ◽  
pp. 1881-1889 ◽  
Author(s):  
Sarah Schwartz Baxter ◽  
Christopher F. Dibble ◽  
Warren C. Byrd ◽  
Jim Carlson ◽  
Charles Russell Mack ◽  
...  
Keyword(s):  
Systems Biology ◽  
Signaling Pathways ◽  
Proteomic Analysis ◽  
Cavernous Malformation ◽  
Cytoskeletal Proteins ◽  
Cerebral Cavernous Malformation

Anin vitroproteomics and systems biology of cerebral cavernous malformation.

The role of micro-computed tomography in forensic investigations

2013 ◽  
Vol 225 (1-3) ◽  
pp. 60-66 ◽  
Author(s):  
G.N. Rutty ◽  
A. Brough ◽  
M.J.P. Biggs ◽  
C. Robinson ◽  
S.D.A. Lawes ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Micro Computed Tomography ◽  
Forensic Investigations

Mobilization Studies in Complement-Deficient Mice Reveal That AMD3100 Mobilization Depends On Complement Cascade Activation and Suggest Involvement of “Membrane Attack Complex - MAC” in Egress of Hematopoietic Stem/Progenitor Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 367-367
Author(s):  
Marcin Wysoczynski ◽  
HakMo Lee ◽  
Rui Liu ◽  
Wan Wu ◽  
Janina Ratajczak, ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Conflicts Of Interest ◽  
Membrane Attack Complex ◽  
Classical Pathway ◽  
Compensatory Mechanism ◽  
Complement Cascade ◽  
Cxcr4 Antagonist ◽  
Hematopoietic Stem ◽  
Deficient Mice

Abstract Abstract 367 We reported that complement cascade (CC) becomes activated in bone marrow (BM) during mobilization of hematopoietic stem/progenitor cells (HSPCs) by immunoglobulin (Ig)-dependent pathway and/or by alternative Ig-independent pathway as seen during G-CSF- or Zymosan mobilization, respectively. As a result, several potent bioactive CC anaphylatoxins (C3 and C5 cleavage fragments) are released that regulate egress of HSPCs (Blood 2003;101,3784; Blood 2004;103,2071; Blood 2005;105,40, Leukemia 2009; in press.). This explains why: i) NOD/SCID and RAG-/- animals that do not activate the Ig-dependent CC classical pathway; ii) C2fB-/- and C3-/- mice that do not activate the classical and alternative CC pathways; and iii) C5-/- mice that do not activate the distal pathway of CC are all poor G-CSF- and/or Zymosan mobilizers. In this study, we evaluated the role of CC in mobilization induced by CXCR4 antagonist AMD3100. We noticed that all CC activation-deficient mice mentioned above, except C5-/- mice, mobilize normally in response to AMD3100 administration. Accordingly, the number of mobilized CD34- SKL cells, leucocytes, and CFU-GM clonogeneic progenitors in mutant mice was similar to wt littermates. More important we observed that AMD3100 mobilization of HSPCs was preceded by a massive egress of leucocytes from BM and that AMD3100 was able to stimulate in these cells i) phosphorylation of MAPKp42/44 and ii) secretion of MMP-9. At the same time, ELISA data to detect CC activation revealed that serum levels of CC cleavage fragments, which were low in the initial phase of AMD3100 mobilization during granulocyte egress, become elevated later during HSPC egress. Thus, our data show that despite a fact that G-CSF and AMD3100 mobilize HSPCs by involving different mechanisms, activation of CC is a common phenomenon occurring during mobilization induced by both compounds. This further supports a pivotal role of CC activation in the egress of HSPCs from BM; however, both compounds activate CC differently. While G-CSF administration initiates CC activation at its proximal C1q-C3 level, AMD3100 induces CC activation at the distal C5 level, pointing to a crucial role of C5 cleavage in executing mobilization. To support this, all mice employed in our studies that display defects in activation of proximal stages of CC (NOD/SCID, RAG, C2fB-/-, and C3-/-) are normal AMD3100 mobilizers. However, C5 is cleavage required for mobilization occurs in the plasma of these animals latter on - directly by proteases released from AMD3100-stimulated granulocytes that egress from the BM as a first wave of mobilized cells. This compensatory mechanism cannot occur from obvious reasons in C5-/- mice. We conclude that AMD3100-directed mobilization similarly as G-CSF-induced one depends on activation of CC; however, AMD3100 in contrast to G-CSF activates CC at distal stages – directly by proteases released from mobilized/activated granulocytes. Cleavage of C5 and release of C5a and desArgC5a create a sinusoid-permissive environment in BM for HSPCs egress. This suggests involvement of both C5 cleavage fragments as well as a potential role of downstream elements of CC activation - membrane attack complex - MAC (C5b-C9) in stem cell mobilization. Therefore, some poor AMD3100 patient responders could possess a defect in activation of the distal steps of CC. Disclosures: No relevant conflicts of interest to declare.

Abstract 196: Polymorphisms in Cerebral Cavernous Malformation Signaling Pathway Genes Associated With Severity of Cerebral Cavernous Malformation Type 1

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Hélène Choquet ◽  
Ludmila Pawlikowska ◽  
Jeffrey Nelson ◽  
Charles E McCulloch ◽  
Amy Akers ◽  
...  
Keyword(s):  
Disease Severity ◽  
Cavernous Malformation ◽  
Cerebral Cavernous Malformation ◽  
Neurological Deficits ◽  
Lesion Count ◽  
Large Lesion ◽  
Genes Encoding ◽  
Dominant Disease ◽  
Familial Cerebral Cavernous Malformation

Objective: Familial cerebral cavernous malformation (CCM) is an autosomal dominant disease caused by mutations in CCM1 , CCM2 or CCM3 , and characterized by multiple brain lesions that can lead to intracerebral hemorrhage (ICH), seizures, and neurological deficits. Carriers of the same mutation can manifest variable symptoms and severity of disease, suggesting the influence of modifiers. As the three CCM proteins form a trimeric complex in vitro and interact with many other proteins, we hypothesized that variants in CCM1-2-3 and in other genes encoding proteins involved in CCM signaling modify disease severity, as manifested by ICH and greater total or large lesion counts. Methods: We analyzed 188 Hispanic CCM1 patients harboring the common Hispanic mutation (CHM, CCM1 Q455X). ICH and lesion counts at enrollment were obtained by clinical assessment and MRI. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 504 variants (MAF≥1%) within +/- 5kb of 42 genes for association with ICH, total and large (≥5 mm in diameter) lesion counts, adjusting for age, gender and family structure. Results: At baseline, 30.3% of CCM1-CHM patients had a history of ICH. Mean total lesion count was 60.1 ± 115.0 (range 0 to 713). Mean large lesion count was 4.9 ± 8.7 (range 0 to 104). Two NTRK1 variants (rs41267423 and rs1800879) as well as SLMAP rs7621574 and PCDHGA1 rs17097189 were significantly associated with ICH ( P ≤0.014). Suggestive associations with ICH ( P ≤0.05) were observed for additional 15 variants in 11 genes. RAP1GAP rs2625408 was associated with both total and large lesion counts ( P ≤0.004) and additional 4 variants in 4 genes were associated with one of these phenotypes. No single variant was associated with both ICH and total or large lesion count; however, different variants in RAP1GAP and KDR genes were associated with all three phenotypes tested. Conclusions: Variants in genes involved in CCM signaling may contribute to variability in CCM1 disease severity. Genotypes that replicate in other cohorts might be useful as predictors in clinical management.

scholarly journals Radiomorphometric Quantitative Analysis of Vasculature Utilizing Micro–Computed Tomography and Vessel Perfusion in the Murine Mandible

2012 ◽  
Vol 5 (4) ◽  
pp. 223-229 ◽  
Author(s):  
Xi Lin Jing ◽  
Aaron S. Farberg ◽  
Laura A. Monson ◽  
Alexis Donneys ◽  
Catherine N. Tchanque-Fossuo ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Quantitative Measure ◽  
Micro Ct ◽  
Vascular Networks ◽  
Sprague Dawley ◽  
Micro Computed Tomography ◽  
Craniofacial Skeleton ◽  
Sprague Dawley Rats ◽  
Quantitative Data Analysis

Purpose Biomechanical, densitometric, and histological analyses have been the mainstay for reproducible outcome measures for investigation of new bone formation and osseous healing. Here we report the addition of radiomorphometric vascular analysis as a quantitative measure of vascularity in the murine mandible. To our knowledge this is the first description of using micro–computed tomography (micro-CT) to evaluate the temporal and spatial pattern of angiogenesis in the craniofacial skeleton. Methods The vessel perfusion technique was performed on 10 Sprague-Dawley rats using Microfil (MV-122, Flow Tech; Carver, MA). After decalcification, hemimandibles were imaged using high-resolution micro-CT. Six separate radiomorphometric vascular metrics were calculated. Results Radiomorphometric values were analyzed using three different thresholds on micro-CT. Experimentally, 1000 Hounsfield units was found to be the optimal threshold for analysis to capture the maximal vascular content of the bone. Data from seven hemimandibles were analyzed. Minimal statistical variance in each of the quantitative measures of vascularity resulted in reproducible metrics for each of the radiomorphometric parameters. Conclusions We have demonstrated that micro-CT vascular imaging provides a robust methodology for evaluation of vascular networks in the craniofacial skeleton. This technique provides 3D quantitative data analysis that differs significantly from laser Doppler and microsphere methods, which simply measure flow. This technique is advantageous over labor-intensive 2D conventional analyses using histology and X-ray microangiography. Our data establish the appropriate thresholding for optimal vascular analyses and provide baseline measurements that can be used to analyze the role of angiogenesis in bone regeneration and repair in the craniofacial skeleton.

scholarly journals Quantitative evaluation of bone-resorptive lesion volume in osteonecrosis of the femoral head using micro-computed tomography

2020 ◽  
Vol 87 (1) ◽  
pp. 75-80 ◽  
Author(s):  
Shoji Baba ◽  
Goro Motomura ◽  
Satoshi Ikemura ◽  
Yusuke Kubo ◽  
Takeshi Utsunomiya ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Femoral Head ◽  
Quantitative Evaluation ◽  
Lesion Volume ◽  
Micro Computed Tomography

scholarly journals Role of the SDF-1/CXCR4 signaling pathway in cartilage and subchondral bone in temporomandibular joint osteoarthritis induced by overloaded functional orthopedics in rats

2020 ◽  
Author(s):  
jing yang ◽  
Yazhen Li ◽  
Ying Liu ◽  
Qiang Zhang ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Temporomandibular Joint ◽  
Signaling Pathway ◽  
Subchondral Bone ◽  
Cartilage Damage ◽  
Mandibular Advancement ◽  
Micro Computed Tomography ◽  
Cxcr4 Signaling ◽  
Skeletal Class Ii ◽  
Temporomandibular Joint Osteoarthritis

Abstract Objectives: To: (i) use a mandibular-advancement appliance in rats to investigate the role of the stromal cell-derived factor/ CXC receptor 4 (SDF-1/CXCR4) signaling pathway in temporomandibular joint osteoarthritis (TMJ OA) induced by overloaded functional orthopedics (OFO); (ii) provide a cellular and molecular basis for efficacious treatment of skeletal class-II malocclusion and avoidance of TMJ OA.Method: Male Sprague–Dawley rats (6 weeks) were divided randomly into control+normal saline (NS), EXP+ADM3100 (SDF-1 antagonist), EXP+NS, and control+ADM3100 groups. Changes in articular cartilage and subchondral bone after TMJ OA in these four groups were observed by hematoxylin and eosin (H&E), Immunofluorescence double staining (IDS), Safranin-O staining, immunohistochemical (IHC) staining, real-time polymerase chain reaction, and micro-computed tomography at 2, 4, and 8 weeks.Results: OFO led to increased expression of SDF-1, CXCR4, and matrix metalloproteinase (MMP)13 and decreased expression of collagen II. The thickness of the hypertrophic cartilage layer was reduced at 4 weeks in the EXP+NS group, and damage to subchondral bone was observed at 2 weeks. Using ADM3100 to inhibit SDF-1 signaling could attenuate expression of MMP13, cartilage damage, and osteoblast differentiation. IDS showed that the areas of expression of SDF-1 and OSX in subchondral bone overlapped.Conclusions: Overloaded functional orthopedics (OFO) induced TMJ-OA. The destruction of subchondral bone in TMJ OA caused by OFO occurred before damage to cartilage. SDF-1/CXCR4 may induce the osteogenic differentiation and cause cartilage degradation in TMJ OA caused by OFO.

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