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مصطلحات موضوعية: 0303 health sciences, biology, Chemistry, Adhesion, 030204 cardiovascular system & hematology, Pharmacological treatment, Cell biology, 03 medical and health sciences, 0302 clinical medicine, Von Willebrand factor, Antithrombotic, Organelle, biology.protein, Secretion, Platelet, Organelle Size, 030304 developmental biology
الوصف: It is long-established that Von Willebrand Factor (VWF) is central to haemostasis and thrombosis. Endothelial VWF is stored in cell-specific secretory granules, Weibel-Palade bodies (WPBs), uniquely rod-like exocytic organelles generated in a wide range of lengths (0.5 to 5.0 µm). It has been shown that WPB size responds to physiological cues and pharmacological treatment and that, under flow, VWF secretion from shortened WPBs produces a dramatic reduction of platelet and plasma VWF adhesion to an endothelial surface. WPB-shortening therefore represents a novel target for antithrombotic therapy acting via modulation of VWF adhesive activity. To this aim, we screened a library of licenced drugs and identified several that prompt WPB size reduction. These compounds therefore constitute a novel set of potentially antithrombotic compounds.SummaryThe size of the endothelial secretory granules that store Von Willebrand Factor correlates with its activity, central to haemostasis and thrombosis. Here, human-licenced drugs that reduce the size of these secretory granules are identified, providing a set of novel potential anti-thrombotic compounds.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_________::6b7153068230f0e9c479b2a572bfa323
https://doi.org/10.1101/2020.05.16.099580 -
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المؤلفون: Zean Mhagna, Antonio Messina, Giovanni Troise, Marco Cirillo, Matteo Saccocci, Niccolò Del Zanna, Francesco Ferraro, Margherita Dalla Tomba, Stefania Blasi, Emmanuel Villa
المصدر: Heart Views, Vol 22, Iss 3, Pp 214-219 (2021)
Heart Views : The Official Journal of the Gulf Heart Associationمصطلحات موضوعية: medicine.medical_specialty, neurofibromatosis, Tricuspid valve, biology, business.industry, cardiac anomalies, Tricuspid valve replacement, Case Report, Perioperative, Regurgitation (circulation), tricuspid valve, medicine.disease, Neurofibromin 1, Cardiac surgery, Surgery, medicine.anatomical_structure, von recklinghausen, RC666-701, biology.protein, Diseases of the circulatory (Cardiovascular) system, Medicine, In patient, Neurofibromatosis, business, cardiac surgery
الوصف: The neurofibromatosis is a large class of different genetic disorders: Neurofibromatosis type 1, type 2, type 3 (or Schwannomatosys), which have different clinical characterization. Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen disease, represents 95% of the total cases. It is a complex autosomal dominant disorder with multisystem involvement, frequently associated to cardiac malformation. We present the case of a 52-years-old male affected by NF-1 with severe tricuspid regurgitation and atrial septal defect (ASD). No previous report about tricuspid valve surgery in NF-1 are available in the literature. A complete perioperative assessment was performed, including dermatologist evaluation, angio-CT scan and trans-esophageal echocardiography. The patient underwent uneventfully tricuspid valve replacement and ASD closure, with no wound complication even at 6-months follow-up. Treating congenital malformation in patient with complex genetic disorders like NF-1 is safe and can be resolutive, permitting to reduce long-term risk of complications for the patients. Preoperative assessments are fundamental, as well as in-hospital care and expertise on congenital heart defects.
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المؤلفون: Daniel F. Cutler, Francesco Ferraro, Jemima J. Burden, Mafalda Lopes-da-Silva, Kimberly J. Harrison-Lavoie, Jessica McCormack
المصدر: Developmental Cell
مصطلحات موضوعية: collagen, AMPK, Golgi Apparatus, von Willebrand factor, AMP-Activated Protein Kinases, Endoplasmic Reticulum, Extracellular matrix, Mice, 0302 clinical medicine, anterograde trafficking, Golgi, Guanine Nucleotide Exchange Factors, Phosphorylation, Cells, Cultured, 0303 health sciences, biology, ADP-Ribosylation Factors, endothelial cells, Cell biology, secretion, Protein Transport, medicine.anatomical_structure, symbols, GBF1, Endothelium, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, symbols.namesake, Von Willebrand factor, Organelle, Human Umbilical Vein Endothelial Cells, medicine, Animals, Humans, Secretion, Molecular Biology, Secretory pathway, 030304 developmental biology, Intracellular Membranes, Cell Biology, Fibroblasts, Golgi apparatus, organelle size, hemostasis, biology.protein, ADP-Ribosylation Factor 1, 030217 neurology & neurosurgery, Developmental Biology
الوصف: Summary How can anterograde membrane trafficking be modulated by physiological cues? A screen of Golgi-associated proteins revealed that the ARF-GEF GBF1 can selectively modulate the ER-Golgi trafficking of prohaemostatic von Willebrand factor (VWF) and extracellular matrix (ECM) proteins in human endothelial cells and in mouse fibroblasts. The relationship between levels of GBF1 and the trafficking of VWF into forming secretory granules confirmed GBF1 is a limiting factor in this process. Further, GBF1 activation by AMPK couples its control of anterograde trafficking to physiological cues; levels of glucose control GBF1 activation in turn modulating VWF trafficking into secretory granules. GBF1 modulates both ER and TGN exit, the latter dramatically affecting the size of the VWF storage organelles, thereby influencing the hemostatic capacity of the endothelium. The role of AMPK as a central integrating element of cellular pathways with intra- and extra-cellular cues can now be extended to modulation of the anterograde secretory pathway.
Graphical Abstract
Highlights • The Arf-GEF GBF1 modulates anterograde trafficking of VWF and ECM proteins • Loss of GBF1 slows ER and TGN exit, producing swollen ER and giant WPBs • Activation of GBF1 via AMPK reduces endothelial WPB size and secretion • Metabolic change alters anterograde trafficking and cargo secretion via AMPK-GBF1
da Silva et al. examine how the secretory pathway is coupled to environmental cues. They show that suppression of GBF1, the GEF for two Golgi Arfs (1 and 4), slows exit from the ER and the TGN. GBF1 can be phosphorylated by AMPK, and metabolic activation or inhibition of AMPK controls anterograde traffic.URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b72b78228b4be90e27a2d44f854e656b
https://doi.org/10.1016/j.devcel.2019.04.006 -
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المصدر: Molecular Biology of the Cell. 19:5072-5081
مصطلحات موضوعية: Small interfering RNA, Protein Conformation, Adaptor Protein Complex 1, Coated vesicle, Nerve Tissue Proteins, Clathrin, Exocytosis, Cell Line, Pregnancy, von Willebrand Factor, Weibel–Palade body, Animals, Humans, Molecular Biology, Secretory pathway, Secretory Pathway, Weibel-Palade Bodies, biology, Endothelial Cells, Articles, Cell Biology, Cell biology, Transcription Factor AP-1, Phenotype, Aftiphilin, biology.protein, Female, RNA Interference, Secretagogue, Carrier Proteins, Biomarkers
الوصف: Formation of secretory organelles requires the coupling of cargo selection to targeting into the correct exocytic pathway. Although the assembly of regulated secretory granules is driven in part by selective aggregation and retention of content, we recently reported that adaptor protein-1 (AP-1) recruitment of clathrin is essential to the initial formation of Weibel-Palade bodies (WPBs) at the trans-Golgi network. A selective co-aggregation process might include recruitment of components required for targeting to the regulated secretory pathway. However, we find that acquisition of the regulated secretory phenotype by WPBs in endothelial cells is coupled to but can be separated from formation of the distinctive granule core by ablation of the AP-1 effectors aftiphilin and γ-synergin. Their depletion by small interfering RNA leads to WPBs that fail to respond to secretagogue and release their content in an unregulated manner. We find that these non-responsive WPBs have density, markers of maturation, and highly multimerized von Willebrand factor similar to those of wild-type granules. Thus, by also recruiting aftiphilin/γ-synergin in addition to clathrin, AP-1 coordinates formation of WPBs with their acquisition of a regulated secretory phenotype.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::90c85183f344ebee87c8840b1ecb00d7
https://doi.org/10.1091/mbc.e08-03-0301 -
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المؤلفون: Rachel E. Sutton, Francesco Ferraro, Michael Laffan, Daniel F. Cutler, Dorian O. Haskard, Alun D. Hughes, Elspeth M. Payne, Nicola H. Dryden, Richard D. Starke, Anna M. Randi, Koralia E. Paschalaki, Thomas A. J. McKinnon
المصدر: Vascular Pharmacology. 56:318-319
مصطلحات موضوعية: Male, Physiology, Angiogenesis, Pharmacology, Biochemistry, Mice, chemistry.chemical_compound, Cell Movement, hemic and lymphatic diseases, Medicine, Aged, 80 and over, Mice, Knockout, Neovascularization, Pathologic, biology, Reverse Transcriptase Polymerase Chain Reaction, Hematology, Middle Aged, Vascular endothelial growth factor, von Willebrand Diseases, Vascular endothelial growth factor A, medicine.anatomical_structure, Molecular Medicine, Female, RNA Interference, Adult, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Endothelium, Immunoblotting, Immunology, Neovascularization, Physiologic, Cell Line, Angiopoietin-2, Angiopoietin, Von Willebrand factor, Vascular Biology, Internal medicine, von Willebrand Factor, Von Willebrand disease, Animals, Humans, Cell Proliferation, Hemostasis, business.industry, Endothelial Cells, Cell Biology, Integrin alphaVbeta3, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, Endocrinology, chemistry, Cancer research, biology.protein, business
الوصف: The regulation of blood vessel formation is of fundamental importance to many physiological processes, and angiogenesis is a major area for novel therapeutic approaches to diseases from ischemia to cancer. A poorly understood clinical manifestation of pathological angiogenesis is angiodysplasia, vascular malformations that cause severe gastrointestinal bleeding. Angiodysplasia can be associated with von Willebrand disease (VWD), the most common bleeding disorder in man. VWD is caused by a defect or deficiency in von Willebrand factor (VWF), a glycoprotein essential for normal hemostasis that is involved in inflammation. We hypothesized that VWF regulates angiogenesis. Inhibition of VWF expression by short interfering RNA (siRNA) in endothelial cells (ECs) caused increased in vitro angiogenesis and increased vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2)–dependent proliferation and migration, coupled to decreased integrin αvβ3 levels and increased angiopoietin (Ang)–2 release. ECs expanded from blood-derived endothelial progenitor cells of VWD patients confirmed these results. Finally, 2 different approaches, in situ and in vivo, showed increased vascularization in VWF-deficient mice. We therefore identify a new function of VWF in ECs, which confirms VWF as a protein with multiple vascular roles and defines a novel link between hemostasis and angiogenesis. These results may have important consequences for the management of VWD, with potential therapeutic implications for vascular diseases.
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المؤلفون: Anna M. Randi, Alun D. Hughes, Daniel F. Cutler, Richard D. Starke, Dorian O. Haskard, Michael Laffan, Thomas A. J. McKinnon, Koralia E. Paschalaki, Francesco Ferraro, Elspeth M. Payne, Nicola H. Dryden
المصدر: Blood. 118:5311-5311
مصطلحات موضوعية: congenital, hereditary, and neonatal diseases and abnormalities, Matrigel, Endothelium, biology, Angiogenesis, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Umbilical vein, medicine.anatomical_structure, Von Willebrand factor, In vivo, hemic and lymphatic diseases, cardiovascular system, Cancer research, medicine, biology.protein, Von Willebrand disease, Progenitor cell, circulatory and respiratory physiology
الوصف: Abstract 5311 Dysregulation of angiogenesis is implicated in many diseases. Von Willebrand factor (VWF), a large plasma glycoprotein essential for normal haemostasis is synthesized by endothelial cells (EC) and megakaryocytes. Raised VWF plasma levels are a risk factor for arterial thrombosis, whilst deficiency of VWF causes Von Willebrand disease (VWD), the most common congenital bleeding disorder in man. VWD can be associated with angiodysplasia, vascular malformations linked to defective angiogenesis which are responsible for intractable bleeding. We recently showed that VWF is involved in angiogenesis. Inhibition of VWF expression in human umbilical vein EC (HUVEC) with specific siRNA resulted in increased in vitro angiogenesis on Matrigel, proliferation and migration. Mechanism studies implicated the endothelial VWF receptor, integrin αvβ3 and the angiogenesis regulator angiopoietin-2. The findings were confirmed in EC from VWD patients and in VWF-deficient mice. Blood outgrowth endothelial cells (BOEC) isolated from peripheral blood of patients with VWD showed decreased VWF release, compared to control BOEC, and increased in vitro angiogenesis, migration and proliferation, similar to what observed with VWF siRNA-treated HUVEC. In vivo studies using the matrigel model and imaging of blood vessels in the ear showed increased angiogenesis and vascular network in VWF-deficient mice compared to controls. Recent studies in patients BOEC and in VWF deficient mice provide new insight into the complexity of this phenotype. We have used the mouse model of post-natal angiogenesis in the retina to carry out detailed analysis of angiogenic networks in the VWF-deficient mouse, and found increased vascular density and defective vascular network. Moreover, using BOEC from patients with type I and type II VWD, we have studied VWF intracellular distribution by immunofluorescence confocal analysis and found patterns of expression that point to a variety of defects in synthesis, storage and secretion. These studies define a new function for VWF, which may have clinical implications for VWD and for patients at risk of CV disease. Moreover, studies with BOEC from VWF patients provide a novel understanding of the physiopathology of this disease. Disclosures: No relevant conflicts of interest to declare.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_________::00ddaabddcb6f1addbbb9e8a259f97e4
https://doi.org/10.1182/blood.v118.21.5311.5311 -
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المؤلفون: Rachel E. Sutton, Anna M. Randi, Michael Laffan, Thomas A. J. McKinnon, Francesco Ferraro, Richard D. Starke, Alun D. Hughes, Elspeth M. Payne, Nicola H. Dryden, Dorian O. Haskard, Daniel F. Cutler, Koralia E. Paschalaki
المصدر: Heart. 97:e7-e7
مصطلحات موضوعية: congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Matrigel, biology, Angiogenesis, business.industry, medicine.disease, Peripheral blood mononuclear cell, Umbilical vein, Endocrinology, Von Willebrand factor, In vivo, hemic and lymphatic diseases, Internal medicine, cardiovascular system, biology.protein, Von Willebrand disease, medicine, Progenitor cell, Cardiology and Cardiovascular Medicine, business, circulatory and respiratory physiology
الوصف: Dysregulation of angiogenesis is implicated in many diseases. Von Willebrand factor (VWF), a large plasma glycoprotein essential for normal haemostasis is synthesised by endothelial cells (EC) and megakaryocytes. Raised VWF plasma levels are a risk factor for arterial thrombosis, while deficiency of VWF causes Von Willebrand disease (VWD), the most common congenital bleeding disorder in man. VWD can be associated with angiodysplasia, vascular malformations linked to defective angiogenesis. We hypothesised that VWF is involved in angiogenesis. To test this hypothesis, we isolated mononuclear cells from peripheral blood of controls and patients with VWD and cultured them to obtain confluent monolayers of blood outgrowth endothelial cells (BOEC). BOEC from VWD patients showed decreased VWF release, consistent with the patients9 clinical data, increased capillary tube formation on Matrigel, migration and proliferation compared to controls. Thus BOEC from VWD patients exhibit enhanced angiogenic properties. Increased angiogenesis was also observed after inhibition of VWF expression in human umbilical vein EC (HUVEC) with specific siRNA. Mechanism studies on VWF siRNA-treated HUVEC implicated the endothelial VWF receptor, integrin α V β3 and the angiogenesis regulator angiopoietin-2. To validate our findings in an in vivo model we studied the VWF-deficient mouse. In vivo Matrigel angiogenesis and imaging of blood vessels in the ear showed increased angiogenesis and vascular network compared to littermate controls. Thus we have identified a novel mechanism for the regulation of angiogenesis and a new function for VWF, which may have clinical implications for VWD and for cardiovascular disease.
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