Modulation of endothelial organelle size as an antithrombotic strategy

Ferraro, Francesco; Patella, Francesca; Costa, Joana R.; Ketteler, Robin; Kriston‐Vizi, Janos; Cutler, Daniel F.

doi:10.1111/jth.15084

Cited by 16 publications

(16 citation statements)

References 61 publications

(165 reference statements)

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“…These are observations that were also made in our CCM1 −/− BOEC model. Despite upregulation of KLF2 in CCM1 −/− BOEC, we did not observe a shortening of WPBs which would have been indicative of reduced activity of primary hemostasis (Ferraro et al, 2016;Ferraro et al, 2020). In fact, we even found slightly longer WPBs in CCM1-depleted ECs.…”

Section: Discussioncontrasting

confidence: 83%

Inactivation of Cerebral Cavernous Malformation Genes Results in Accumulation of von Willebrand Factor and Redistribution of Weibel-Palade Bodies in Endothelial Cells

Much

Sendtner

Schwefel

et al. 2021

Front. Mol. Biosci.

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Cerebral cavernous malformations are slow-flow thrombi-containing vessels induced by two-step inactivation of the CCM1, CCM2 or CCM3 gene within endothelial cells. They predispose to intracerebral bleedings and focal neurological deficits. Our understanding of the cellular and molecular mechanisms that trigger endothelial dysfunction in cavernous malformations is still incomplete. To model both, hereditary and sporadic CCM disease, blood outgrowth endothelial cells (BOECs) with a heterozygous CCM1 germline mutation and immortalized wild-type human umbilical vein endothelial cells were subjected to CRISPR/Cas9-mediated CCM1 gene disruption. CCM1−/− BOECs demonstrated alterations in cell morphology, actin cytoskeleton dynamics, tube formation, and expression of the transcription factors KLF2 and KLF4. Furthermore, high VWF immunoreactivity was observed in CCM1−/− BOECs, in immortalized umbilical vein endothelial cells upon CRISPR/Cas9-induced inactivation of either CCM1, CCM2 or CCM3 as well as in CCM tissue samples of familial cases. Observer-independent high-content imaging revealed a striking reduction of perinuclear Weibel-Palade bodies in unstimulated CCM1−/− BOECs which was observed in CCM1+/− BOECs only after stimulation with PMA or histamine. Our results demonstrate that CRISPR/Cas9 genome editing is a powerful tool to model different aspects of CCM disease in vitro and that CCM1 inactivation induces high-level expression of VWF and redistribution of Weibel-Palade bodies within endothelial cells.

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Section: Discussioncontrasting

confidence: 83%

Inactivation of Cerebral Cavernous Malformation Genes Results in Accumulation of von Willebrand Factor and Redistribution of Weibel-Palade Bodies in Endothelial Cells

Much

Sendtner

Schwefel

et al. 2021

Front. Mol. Biosci.

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“…This analysis revealed that Golgi elements were almost exclusively of sizes 1l and 2l, closely matching the distribution of WPB size classes (Figure 3E). These data are consistent with repeated observations that the Golgi ribbon is necessary to the formation of long WPBs (29,32,39); most importantly, they strongly suggest that even in the absence of microtubules, the vertebrate Golgi is not reduced exclusively to individual mini-stacks, but that around 50% of the Golgi objects generated by nocodazole treatment are size consistent with mini-stack dimers.…”

Section: Q-wpb Instabilitysupporting

confidence: 90%

“…This "breathing" would make the Golgi ribbon a highly dynamic structure, capable of promptly responding to signals that require its rearrangement, such as re-positioning and re-orientation during migration and directed secretion (23,45,46). It is possible that such a structural organization may not be universal to vertebrate cells, but rather reflect an endothelial adaptation of the Golgi ribbon to the need for WPB production, providing a flexible system capable of modulating the size of these organelles in response to environmental and pharmacological cues (29,34,39,41). However, the above-mentioned evidence of similar dimers present in HeLa cells (43) suggests that this is a more widespread feature.…”

Section: Discussionmentioning

confidence: 99%

Structure modeling hints at a granular organization of the Vertebrate Golgi ribbon

Page

McCormack

Silva

et al. 2021

Preprint

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Vertebrate cells display a specific Golgi apparatus architecture, known as the ribbon, where the functional subunits, the mini-stacks, are linked into a tri-dimensional network. The importance of the ribbon architecture is underscored by evidence of its disruption in a host of diseases, but just how it relates to the biological Golgi functions remains unclear. Are all the connections between mini-stacks functionally equal? Is the local structure of the ribbon of functional importance? These are difficult questions to address, due to the lack of a secretory cargo providing a quantifiable readout of the functional output of ribbon-embedded mini-stacks. Endothelial cells produce rod-shaped secretory granules, the Weibel-Palade bodies (WPB), whose von Willebrand Factor (VWF) cargo is central to hemostasis. In these cells, the Golgi apparatus exerts a dual control on WPB size at both mini-stack and ribbon levels. Mini-stack dimensions delimit the size of VWF boluses while the ribbon architecture allows their linear co-packaging at the trans-Golgi network generating WPBs of different lengths. This Golgi/WPB size relationship lends itself to mathematical analysis. Here, different ribbon structures were modeled and their predicted effects on WPB size distribution compared to the ground truth of experimental data. Strikingly, the best-fitting model describes a Golgi ribbon made by linked subunits corresponding to differentially functioning monomer and dimer mini-stacks. These results raise the intriguing possibility that the fine-grained structure of the Golgi ribbon is more complex than previously thought.

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“…VWF, including its production and binding to GPIb, collagen and Glycoprotein IIbIIIa, as well as ADAMTS13, have been well recognized as potential therapeutic targets within management of vascular events and endothelial dysfunction. Targeting a reduction in the size of Weibel–Palade bodies, the production site of VWF, has been shown to inhibit VWF pro-haemostatic potential [ 60 ]. This may be a potential adjunctive therapy to anti-thrombotic therapies in arterial vascular events, or also for the anti-thrombotic therapy of disseminated intravascular coagulation, which has also been found to be associated with high levels of VWF [ 61 ].…”

Section: Potential Therapeutic Targetsmentioning

confidence: 99%

The Intriguing Relationships of von Willebrand Factor, ADAMTS13 and Cardiac Disease

Reardon

Pasalic

Favaloro

2021

JCDD

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von Willebrand factor (VWF) is an adhesive protein involved in primary hemostasis and facilitates platelet adhesion to sites of vascular injury, thereby promoting thrombus formation. VWF exists in plasma as multimers of increasing size, with the largest (high molecular weight; HMW) expressing the greatest functional activity. A deficiency of VWF is associated with a bleeding disorder called von Willebrand disease (VWD), whereas an excess of VWF, in particular the HMW forms, is associated with thrombosis. ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif-13), also known as VWF-cleaving protease, functions to moderate the activity of VWF by cleaving multimers of VWF and limiting the expression of the largest multimers of VWF. A deficiency of ADAMTS13 is therefore associated with an excess of (HMW forms of) VWF, and thus thrombosis. Indeed, any disturbance of the VWF/ADAMTS13 ratio or ‘axis’ may be associated with pathophysiological processes, including prothrombotic tendency. However, both thrombosis or bleeding may be associated with such disturbances, depending on the presenting events. This review evaluates the relationship of VWF and ADAMTS13 with cardiac disease, including cardiac failure, and associated pathophysiology.

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Modulation of endothelial organelle size as an antithrombotic strategy

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 16 publications

References 61 publications

Inactivation of Cerebral Cavernous Malformation Genes Results in Accumulation of von Willebrand Factor and Redistribution of Weibel-Palade Bodies in Endothelial Cells

Inactivation of Cerebral Cavernous Malformation Genes Results in Accumulation of von Willebrand Factor and Redistribution of Weibel-Palade Bodies in Endothelial Cells

Structure modeling hints at a granular organization of the Vertebrate Golgi ribbon

The Intriguing Relationships of von Willebrand Factor, ADAMTS13 and Cardiac Disease

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