scholarly journals Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican

2020 ◽  
Vol 217 (10) ◽  
Author(s):  
Courtney C. Hong ◽  
Alan T. Tang ◽  
Matthew R. Detter ◽  
Jaesung P. Choi ◽  
Rui Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Wild Type ◽  
Lesion Formation ◽  
Cavernous Malformations ◽  
A Cell ◽  
Early Lesion

Cerebral cavernous malformations (CCMs) form following loss of the CCM protein complex in brain endothelial cells due to increased endothelial MEKK3 signaling and KLF2/4 transcription factor expression, but the downstream events that drive lesion formation remain undefined. Recent studies have revealed that CCM lesions expand by incorporating neighboring wild-type endothelial cells, indicative of a cell nonautonomous mechanism. Here we find that endothelial loss of ADAMTS5 reduced CCM formation in the neonatal mouse model. Conversely, endothelial gain of ADAMTS5 conferred early lesion genesis in the absence of increased KLF2/4 expression and synergized with KRIT1 loss of function to create large malformations. Lowering versican expression reduced CCM burden, indicating that versican is the relevant ADAMTS5 substrate and that lesion formation requires proteolysis but not loss of this extracellular matrix protein. These findings identify endothelial secretion of ADAMTS5 and cleavage of versican as downstream mechanisms of CCM pathogenesis and provide a basis for the participation of wild-type endothelial cells in lesion formation.

scholarly journals The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3

2015 ◽  
Vol 112 (46) ◽  
pp. 14284-14289 ◽  
Author(s):  
Xavier Cullere ◽  
Eva Plovie ◽  
Paul M. Bennett ◽  
Calum A. MacRae ◽  
Tanya N. Mayadas
Keyword(s):  
Endothelial Cells ◽  
Cavernous Malformation ◽  
Body Axis ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Cavernous Malformations ◽  
Downstream Target ◽  
Density Flow

Three genes, CCM1, CCM2, and CCM3, interact genetically and biochemically and are mutated in cerebral cavernous malformations (CCM). A recently described member of this CCM family of proteins, CCM2-like (CCM2L), has high homology to CCM2. Here we show that its relative expression in different tissues differs from that of CCM2 and, unlike CCM2, the expression of CCM2L in endothelial cells is regulated by density, flow, and statins. In vitro, both CCM2L and CCM2 bind MEKK3 in a complex with CCM1. Both CCM2L and CCM2 interfere with MEKK3 activation and its ability to phosphorylate MEK5, a downstream target. The in vivo relevance of this regulation was investigated in zebrafish. A knockdown of ccm2l and ccm2 in zebrafish leads to a more severe “big heart” and circulation defects compared with loss of function of ccm2 alone, and also leads to substantial body axis abnormalities. Silencing of mekk3 rescues the big heart and body axis phenotype, suggesting cross-talk between the CCM proteins and MEKK3 in vivo. In endothelial cells, CCM2 deletion leads to activation of ERK5 and a transcriptional program that are downstream of MEKK3. These findings suggest that CCM2L and CCM2 cooperate to regulate the activity of MEKK3.

scholarly journals CCM2 deficient endothelial cells undergo a mechano-dependent reprogramming into senescence associated secretory phenotype used to recruit endothelial and immune cells

2021 ◽  
Author(s):  
Daphné Raphaëlle Vannier ◽  
Apeksha Shapeti ◽  
Florent Chuffart ◽  
Emmanuelle Planus ◽  
Sandra Manet ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Cerebrovascular Disease ◽  
Immune Cells ◽  
Cerebral Cavernous Malformations ◽  
Wild Type ◽  
Cellular Mechanics ◽  
Cavernous Malformations ◽  
Secretory Phenotype ◽  
The Brain

AbstractCerebral Cavernous Malformations (CCM) is a cerebrovascular disease in which stacks of dilated haemorrhagic capillaries form focally in the brain. Whether and how defective mechanotransduction, cellular mosaicism and inflammation interplay to sustain the progression of CCM diseases is unknown. Here, we reveal that CCM1- and CCM2-silenced endothelial cells enter into senescence associated with secretory phenotype (SASP) that they use to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells. Further, we demonstrate that this SASP is driven by the mechanical and molecular disorders provoked by ROCKs dysfunctions. By this, we identify CCM1/2 and ROCKs as parts of a scaffold controlling senescence, bringing new insights into the emerging field of the control of aging by cellular mechanics. This discovery reconciles the dysregulated traits of CCM1/2-deficient endothelial cells into a unique mechano-dependent endothelial fate that links perturbed mechanics to microenvironment remodelling and long-range activation of endothelial and immune cells.

scholarly journals Non cell-autonomous effect of astrocytes on cerebral cavernous malformations

2021 ◽  
Author(s):  
Miguel Alejandro Lopez-Ramirez ◽  
Shady Ibrahim Soliman ◽  
Preston Hale ◽  
Catherine Chinhchu Lai ◽  
Angela Pham ◽  
...  
Keyword(s):  
Target Gene ◽  
Critical Role ◽  
Vascular Lesion ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Lesion Formation ◽  
Lesion Development ◽  
Cavernous Malformations ◽  
Cox 2 ◽  
Endothelial Nitric Oxide

AbstractCerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we report that proliferative astrocytes play a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2 and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilizes HIF-1α in astrocytes, resulting in increased VEGF production and expression of a “hypoxic” program under normoxic conditions. We show that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1α target gene and a known component of the hypoxic program, contributes to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevents progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.

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

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 704
Author(s):  
Giulia Riolo ◽  
Claudia Ricci ◽  
Stefania Battistini
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Cellular Level ◽  
Vascular Lesions ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Cavernous Malformations ◽  
Familial Form ◽  
Protein Functions

Cerebral cavernous malformations (CCMs) are vascular lesions that affect predominantly microvasculature in the brain and spinal cord. CCM can occur either in sporadic or familial form, characterized by autosomal dominant inheritance and development of multiple lesions throughout the patient’s life. Three genes associated with CCM are known: CCM1/KRIT1 (krev interaction trapped 1), CCM2/MGC4607 (encoding a protein named malcavernin), and CCM3/PDCD10 (programmed cell death 10). All the mutations identified in these genes cause a loss of function and compromise the protein functions needed for maintaining the vascular barrier integrity. Loss of function of CCM proteins causes molecular disorganization and dysfunction of endothelial adherens junctions. In this review, we provide an overall vision of the CCM pathology, starting with the genetic bases of the disease, describing the role of the proteins, until we reach the cellular level. Thus, we summarize the genetics of CCM, providing a description of CCM genes and mutation features, provided an updated knowledge of the CCM protein structure and function, and discuss the molecular mechanisms through which CCM proteins may act within endothelial cells, particularly in endothelial barrier maintenance/regulation and in cellular signaling.

Thrombospondin-4 knockout in hypertension protects small-artery endothelial function but induces aortic aneurysms

2016 ◽  
Vol 310 (11) ◽  
pp. H1486-H1493 ◽  
Author(s):  
Teresa Palao ◽  
Catarina Rippe ◽  
Henk van Veen ◽  
Ed VanBavel ◽  
Karl Swärd ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Matrix Protein ◽  
Pressure Overload ◽  
Aortic Aneurysms ◽  
Endoplasmic Reticulum Stress Response ◽  
Extracellular Matrix Protein ◽  
Ang Ii ◽  
Wild Type ◽  
Resistance Arteries ◽  
Thrombospondin 4

Thrombospondin-4 (TSP-4) is a multidomain calcium-binding protein that has both intracellular and extracellular functions. As an extracellular matrix protein, it is involved in remodeling processes. Previous work showed that, in the cardiovascular system, TSP-4 expression is induced in the heart in response to experimental pressure overload and infarction injury. Intracellularly, it mediates the endoplasmic reticulum stress response in the heart. In this study, we explored the role of TSP-4 in hypertension. For this purpose, wild-type and TSP-4 knockout ( Thbs4 −/−) mice were treated with angiotensin II (ANG II). Hearts from ANG II-treated Thbs4 −/− mice showed an exaggerated hypertrophic response. Interestingly, aortas from Thbs4 −/− mice treated with ANG II showed a high incidence of aneurysms. In resistance arteries, ANG II-treated wild-type mice showed impaired endothelial-dependent relaxation. This was not observed in ANG II-treated Thbs4 −/− mice or in untreated controls. No differences were found in the passive pressure-diameter curves or stress-strain relationships, although ANG II-treated Thbs4 −/− mice showed a tendency to be less stiff, associated with thicker diameters of the collagen fibers as revealed by electron microscopy. We conclude that TSP-4 plays a role in hypertension, affecting cardiac hypertrophy, aortic aneurysm formation, as well as endothelial-dependent relaxation in resistance arteries.

scholarly journals Suppressive Effects of Sulforaphane on TGFBIp-mediated Sepsis

2017 ◽  
Vol 12 (10) ◽  
pp. 1934578X1701201 ◽  
Author(s):  
In-Chul Lee ◽  
Jong-Sup Bae
Keyword(s):  
Endothelial Cells ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Umbilical Vein ◽  
Cecal Ligation ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Protein ◽  
Experimental Sepsis

Sulforaphane (SFN) is produced when the enzyme myrosinase transforms glucoraphanin upon damage to the plant such as from chewing and effective in preventing carcinogenesis, diabetes, and inflammatory responses. Transforming growth factor β-induced protein (TGFBIp) is an extracellular matrix protein whose expression in several cell types is greatly increased by TGF-β. TGFBIp is released by human umbilical vein endothelial cells (HUVECs) and functions as a mediator of experimental sepsis. We hypothesized that SFN could reduce TGFBIp-mediated severe inflammatory responses in human endothelial cells and mice. Here, we investigated the anti-septic effects and underlying mechanisms of SFN against TGFBIp-mediated septic responses. SFN effectively inhibited lipopolysaccharide-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. In addition, SFN suppressed cecal ligation and puncture (CLP)-induced sepsis lethality and pulmonary injury. In conclusion, SFN suppressed TGFBIp-mediated and CLP-induced septic responses. Therefore, SFN could be a potential therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the TGFBIp signaling pathway.

scholarly journals Thrombospondin 1 mediates renal dysfunction in a mouse model of high-fat diet-induced obesity

2013 ◽  
Vol 305 (6) ◽  
pp. F871-F880 ◽  
Author(s):  
Wenpeng Cui ◽  
Hasiyeti Maimaitiyiming ◽  
Xinyu Qi ◽  
Heather Norman ◽  
Shuxia Wang
Keyword(s):  
Mouse Model ◽  
Renal Dysfunction ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Kidney Diseases ◽  
Extracellular Matrix Protein ◽  
Obese Mouse ◽  
Wild Type ◽  
Thrombospondin 1

Obesity is prevalent worldwide and is a major risk factor for many diseases including renal complications. Thrombospondin 1 (TSP1), a multifunctional extracellular matrix protein, plays an important role in diabetic kidney diseases. However, whether TSP1 plays a role in obesity-related kidney disease is unknown. In the present studies, the role of TSP1 in obesity-induced renal dysfunction was determined by using a diet-induced obese mouse model. The results demonstrated that TSP1 was significantly upregulated in the kidney from obese mice. The increased TSP1 was localized in the glomerular mesangium as well as in the tubular system from obese wild-type mice. Obese wild-type mice developed renal hypertrophy and albuminuria, which was associated with increased kidney macrophage infiltration, augmented kidney inflammation, and activated transforming growth factor (TGF)-β signaling and renal fibrosis. In contrast, obese TSP1-deficient mice did not develop these kidney damages. Furthermore, in vitro studies demonstrated that leptin treatment stimulated the expression of TSP1, TGF-β1, fibronectin, and collagen type IV in mesangial cells isolated from wild-type mice. These leptin-stimulated effects were abolished in TSP1-deficient mesangial cells. Taken together, these data suggest that TSP1 is an important mediator for obesity- or hyperleptinemia-induced kidney dysfunction.

scholarly journals Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

2011 ◽  
Vol 208 (9) ◽  
pp. 1835-1847 ◽  
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.

scholarly journals Pericyte-derived vitronectin regulates blood-CNS barrier function via integrin signaling

2021 ◽  
Author(s):  
Swathi Ayloo ◽  
Christopher Gallego Lazo ◽  
Shenghuan Sun ◽  
Wei Zhang ◽  
Bianxiao Cui ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Barrier Function ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Integrin Signaling ◽  
Integrin Receptor ◽  
Perivascular Cells ◽  
Extrinsic Factors ◽  
Genetic Ablation ◽  
Integrin Α5

Blood-central nervous system (CNS) barriers are physiological interfaces separating the neural tissue from circulating blood and are essential for neuronal function and cellular homeostasis. Endothelial cells that form the walls of CNS blood vessels constitute these barriers but barrier properties are not intrinsic to these cells; rather they are actively induced and maintained by the surrounding CNS microenvironment. Notably, the abluminal surface of CNS capillary endothelial cells is ensheathed by pericytes and astrocytic endfeet. However, the specific extrinsic factors from these perivascular cells that regulate barrier integrity are largely unknown. Here, we establish vitronectin, an extracellular matrix protein secreted specifically by CNS pericytes as an essential factor in regulating blood-CNS barrier function via interactions with its integrin receptor in adjacent endothelial cells. Genetic ablation of vitronectin results in leaky blood-CNS barriers, despite having normal pericyte coverage and vascular patterning. Electron microscopy reveals increased transcytosis in endothelial cells of Vtn−/− mice without functional defects in tight-junctions. We further demonstrate that vitronectin binding to integrin receptors is essential for barrier function, as mice harboring a point mutation in vitronectin that specifically abolishes integrin binding, VtnRGE, phenocopy the barrier defects in Vtn−/− mice. Furthermore, endothelial-specific deletion of integrin α5, an RGD-ligand binding integrin receptor that is expressed in CNS endothelial cells, also results in similar blood-CNS barrier defects as observed in Vtn−/− and VtnRGE mice. Finally, integrin α5 activation by vitronectin inhibits transcytosis in endothelial cells and vitronectin-integrin α5 signaling regulates barrier function independent of the caveolae pathway. These results demonstrate that signaling from perivascular cells to endothelial cells via ligand-receptor interactions is a key mechanism to regulate barrier permeability.SummaryVitronectin-integrin signaling between pericytes and CNS endothelial cells regulates blood-CNS barrier function

scholarly journals Extracellular Matrix Protein Tenascin C Increases Phagocytosis Mediated by CD47 Loss of Function in Glioblastoma

2019 ◽  
Vol 79 (10) ◽  
pp. 2697-2708 ◽  
Author(s):  
Ding Ma ◽  
Senquan Liu ◽  
Bachchu Lal ◽  
Shuang Wei ◽  
Shuyan Wang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Loss Of Function ◽  
Tenascin C
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