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1.
Normal mechanisms of platelet function 总被引:12,自引:0,他引:12
2.
Epinephrine is the only physiological platelet activator which induces platelet aggregation without a preceding change in platelet shape. The reason why epinephrine cannot induce this shape change is not known. Electron microscopically, we could show that during the first phase of epinephrine-induced platelet aggregation, the platelet aggregate is composed of discoid platelets, lying in rather loose contact with neighbouring platelets. During the second wave of epinephrine-induced aggregation (this is when thromboxane (TX)A(2) production has taken place), platelets have completely lost their discoid shape and are very tightly bound. In EDTA-platelet rich plasma (PRP), we could demonstrate a clear synergistic action of epinephrine 10-20 μM on the first phase of shape change (disc-to-sphere transformation), induced by low concentrations of arachidonic acid (AA), collagen, adenosine diphosphate (ADP) and platelet activating factor (PAF). In combination with moderate concentrations of AA or collagen, epinephrine induced a clear aggregation-independent secretion of platelet granules, which in the absence of epinephrine, only takes place with higher inducer concentrations. All these synergistic actions could be demonstrated in the aggregometer and electron microscopically. To explain these findings, we hypothesize that the inability of epinephrine to induce a shape change that precedes aggregation is due to slow generation of TXA(2) which is only formed as a positive feedback mechanism of aggregation. This TXA(2) will bind to its own receptor and produce a shape change coinciding with the second wave of epinephrine-induced aggregation. Collagen, in contrast, induces very rapid TXA(2) generation, causing Ca(2+) mobilization and myosin light chain-phosphorylation, leading to shape change, clearly before aggregation starts. 相似文献
3.
High and long‐term von Willebrand factor expression after Sleeping Beauty transposon‐mediated gene therapy in a mouse model of severe von Willebrand disease 下载免费PDF全文
I. Portier K. Vanhoorelbeke S. Verhenne I. Pareyn N. Vandeputte H. Deckmyn D. S. Goldenberg H. B. Samal M. Singh Z. Ivics Z. Izsvák S. F. De Meyer 《Journal of thrombosis and haemostasis》2018,16(3):592-604
Essentials
- von Willebrand disease (VWD) is the most common inherited bleeding disorder.
- Gene therapy for VWD offers long‐term therapy for VWD patients.
- Transposons efficiently integrate the large von Willebrand factor (VWF) cDNA in mice.
- Liver‐directed transposons support sustained VWF expression with suboptimal multimerization.
Summary
Background
Type 3 von Willebrand disease (VWD) is characterized by complete absence of von Willebrand factor (VWF). Current therapy is limited to treatment with exogenous VWF/FVIII products, which only provide a short‐term solution. Gene therapy offers the potential for a long‐term treatment for VWD.Objectives
To develop an integrative Sleeping Beauty (SB) transposon‐mediated VWF gene transfer approach in a preclinical mouse model of severe VWD.Methods
We established a robust platform for sustained transgene murine VWF (mVWF) expression in the liver of Vwf?/? mice by combining a liver‐specific promoter with a sandwich transposon design and the SB100X transposase via hydrodynamic gene delivery.Results
The sandwich SB transposon was suitable to deliver the full‐length mVWF cDNA (8.4 kb) and supported supra‐physiological expression that remained stable for up to 1.5 years after gene transfer. The sandwich vector stayed episomal (~60 weeks) or integrated in the host genome, respectively, in the absence or presence of the transposase. Transgene integration was confirmed using carbon tetrachloride‐induced liver regeneration. Analysis of integration sites by high‐throughput analysis revealed random integration of the sandwich vector. Although the SB vector supported long‐term expression of supra‐physiological VWF levels, the bleeding phenotype was not corrected in all mice. Long‐term expression of VWF by hepatocytes resulted in relatively reduced amounts of high‐molecular‐weight multimers, potentially limiting its hemostatic efficacy.Conclusions
Although this integrative platform for VWF gene transfer is an important milestone of VWD gene therapy, cell type‐specific targeting is yet to be achieved.4.
Although platelets are the smallest cells in the blood, they are implied in various processes ranging from immunology and oncology to thrombosis and hemostasis. Many large-scale screening programs, genome-wide association, and "omics" studies have generated lists of genes and loci that are probably involved in the formation or physiology of platelets under normal and pathologic conditions. This creates an increasing demand for new and improved model systems that allow functional assessment of the corresponding gene products in vivo. Such animal models not only render invaluable insight in the platelet biology, but in addition, provide improved test systems for the validation of newly developed anti-thrombotics. This review summarizes the most important models to generate transgenic platelets and to study their influence on platelet physiology in vivo. Here we focus on the zebrafish morpholino oligonucleotide technology, the (platelet-specific) knockout mouse, and the transplantation of genetically modified human or murine platelet progenitor cells in myelo-conditioned mice. The various strengths and pitfalls of these animal models are illustrated by recent examples from the platelet field. Finally, we highlight the latest developments in genetic engineering techniques and their possible application in platelet research. 相似文献
5.
Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb,GPIIb/IIIa,and von Willebrand Factor 下载免费PDF全文
Lars Burdorf Andrea Riner Elana Rybak Isabelle I. Salles Simon F. De Meyer Aakash Shah Kevin J. Quinn Donald Harris Tianshu Zhang Dawn Parsell Franchesca Ali Evan Schwartz Elizabeth Kang Xiangfei Cheng Evelyn Sievert Yuming Zhao Gheorghe Braileanu Carol J. Phelps David L. Ayares Hans Deckmyn Richard N. Pierson III Agnes M. Azimzadeh 《Xenotransplantation》2016,23(3):222-236
6.
Thierry Poynard Valentina Peta Olivier Deckmyn Mona Munteanu Joseph Moussalli Yen Ngo Marika Rudler Pascal Lebray Raluca Pais Luminita Bonyhay Frederic Charlotte Vincent Thibault Laetitia Fartoux Olivier Lucidarme Daniel Eyraud Olivier Scatton Eric Savier Marc Antoine Valantin An Ngo Fabienne Drane Olivier Rosmorduc Franoise Imbert‐Bismut Chantal Housset Dominique Thabut Vlad Ratziu 《Alimentary pharmacology & therapeutics》2019,49(3):308-320
7.
Crucial Role for Endothelial Cell α2β1 Integrin Receptor Clustering in Collagen-Induced Angiogenesis
Kevin R. Turner Christopher Adams Stephanie Staelens Hans Deckmyn James San Antonio 《Anatomical record (Hoboken, N.J. : 2007)》2020,303(6):1604-1618
Angiogenesis is a crucial mechanism of vascular growth and regeneration that requires biosynthesis and cross-linking of collagens in vivo and is induced by collagen in vitro. Here, we use an in vitro model in which apical Type I collagen gels rapidly induce angiogenesis in endothelial monolayers. We extend previous studies demonstrating the importance of the endothelial α2β1 integrin, a key collagen receptor, in angiogenesis by investigating the roles of receptor clustering and conformational activation. Immunocytochemical localization of α2β1 integrins in endothelial monolayers showed a concentration of integrins along cell–cell borders. After inducing angiogenesis with collagen, the receptors redistributed to apical cell surfaces, aligning with collagen fibers, which were also redistributed during angiogenesis. Levels of conformationally activated α2β1 integrins were unchanged during angiogenesis and undetected on endothelial cells binding collagen in suspension. We mimicked the polyvalency of collagen fibrils using antibody-coated polystyrene beads to cluster endothelial cell surface α2β1 integrins, which induced rapid angiogenesis in the absence of collagen gels. Clustering of αvβ3 integrins and PECAM-1 but not of α1 integrins also induced angiogenesis. Soluble antibodies alone had no effect. Thus, the angiogenic property of collagen may reside in its ability to ligate and cluster cell surface receptors such as α2β1 integrins. Furthermore, synthetic substrates that promote the clustering of select endothelial cell surface receptors mimic the angiogenic properties of Type I collagen and may have applications in promoting vascularization of engineered tissues. Anat Rec, 2019. © 2019 American Association for Anatomy 相似文献
8.
9.
Thromboxane A2 and prostacyclin do not modulate the systemic hemodynamic response to cold in humans 总被引:1,自引:0,他引:1
P Gresele H Bounameaux J Arnout J L Perez-Requejo H Deckmyn J Vermylen 《The Journal of laboratory and clinical medicine》1985,106(5):534-541
The immersion of a limb in a mixture of water and ice induces in normal humans an initial vasoconstriction mediated mainly by catecholamine release. In some studies the cold pressor test was associated with an increase in vasoconstrictor thromboxane A2 and in vasodilating prostacyclin. Dazoxiben hydrochloride, a thromboxane synthase inhibitor, has been reported to suppress cold-induced vasoconstriction. We compared in a double-blind, crossover, placebo-controlled study the effects of indomethacin (a cyclooxygenase inhibitor), dazoxiben hydrochloride, and BM13.177 (a novel thromboxane receptor antagonist) on the changes in cutaneous vascular resistance and arterial blood pressure induced by cold in 12 healthy volunteers. Cold challenge produced an increase in blood pressure and an initial decrease in finger blood flow, reflecting an increase in cutaneous vascular resistance. Neither effective suppression of thromboxane A2 generation or of the effects of thromboxane A2 on platelets by the three active treatments nor increase in prostacyclin generation after ingestion of dazoxiben hydrochloride modified the hemodynamic response to cold. In conclusion, thromboxane A2 and prostacyclin do not play a significant role in the modulation of the systemic hemodynamic response to cold. In addition, thromboxane receptor antagonism in normal humans does not influence basal blood pressure. 相似文献
10.
Amplified endogenous plasmin activity resolves acute thrombotic thrombocytopenic purpura in mice 下载免费PDF全文
C. Tersteeg B. S. Joly A. Gils R. Lijnen H. Deckmyn P. J. Declerck B. Plaimauer P. Coppo A. Veyradier C. Maas S. F. De Meyer K. Vanhoorelbeke 《Journal of thrombosis and haemostasis》2017,15(12):2432-2442
Essentials
- Plasmin is able to proteolyse von Willebrand factor.
- It was unclear if plasmin influences acute thrombotic thrombocytopenic purpura (TTP).
- Plasmin levels are increased during acute TTP though suppressed via plasmin(ogen) inhibitors.
- Allowing amplified endogenous plasmin activity in mice results in resolution of TTP signs.