Regulated von Willebrand Factor Secretion Is Associated With Agonist-Specific Patterns of Cytoskeletal Remodeling in Cultured Endothelial Cells

Vischer, Ulrich M.; Barth, Holger; Wollheim, Claes B.

doi:10.1161/01.atv.20.3.883

Cited by 77 publications

(90 citation statements)

References 30 publications

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“…6B). Microtubule-dependent transport of WPb to the plasma membrane is consistent with the observation that microtubule disruption blocks vWF secretion (Sinha and Wagner, 1987;Vischer et al, 2000).…”

Section: Journal Of Cell Science 116 (19)supporting

confidence: 86%

“…The pro-inflammatory adhesive protein von Willebrand factor (vWF) is stored in unique large tubular organelles (1-3 µm long, 0.1-0.2 µm diameter) called Weibel-Palade bodies (WPb) (van Mourik et al, 2002;Weibel and Palade, 1964). Disruption of microtubules blocks the regulated secretion of both tPA (Santell et al, 1992) and vWF (Sinha and Wagner, 1987;Vischer et al, 2000), suggesting that the microtubule cytoskeleton plays a central role in the processing and/or transport of tPA and vWF. WPb are members of the family of lysosome-related organelles, which includes the pigment granules of melanocytes (Marks and Seabra, 2001).…”

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confidence: 99%

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Interaction of the actin cytoskeleton with microtubules regulates secretory organelle movement near the plasma membrane in human endothelial cells

Manneville¹,

Etienne-Manneville

Skehel

et al. 2003

Journal of Cell Science

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The role of cytoskeletal elements in regulating transport and docking steps that precede exocytosis of secretory organelles is not well understood. We have used Total Internal Reflection Fluorescence (TIRF) microscopy to visualize the three-dimensional motions of secretory organelles near the plasma membrane in living endothelial cells. Weibel-Palade bodies (WPb), the large tubular storage organelles for von Willebrand factor, were labelled with Rab27a-GFP. By contrast, green fluorescent protein (GFP)-tagged tissue-type plasminogen activator (tPA-GFP) labelled submicron vesicular organelles. Both populations of GFP-labelled organelles underwent stimulated exocytosis. The movement of these morphologically distinct organelles was measured within the evanescent field that penetrated the first 200 nm above the plasma membrane. WPb and tPA-GFP vesicles displayed long-range bidirectional motions and short-range diffusive-like motions. Rotating and oscillating WPb were also observed. TIRF microscopy enabled us to quantify the contribution of actin and microtubules and their associated motors to the organelle motions close to the plasma membrane. Long-range motions, as well as WPb rotations and oscillations, were microtubule-and kinesin-dependent. Disruption of the actin cytoskeleton and inhibition of myosin motors increased the number of long-range motions and, in the case of WPb, their velocity. The actin and microtubules had opposite effects on the mobility of organelles undergoing short-range motions. Actin reduced the mobility and range of motion of both WPb and tPA vesicles, whereas microtubules and kinesin motors increased the mobility of WPb. The results show that the dynamics of endothelial secretory organelles close to the plasma membrane are controlled by the opposing roles of the microtubule and actin cytoskeletal transport systems.

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Section: Journal Of Cell Science 116 (19)supporting

confidence: 86%

mentioning

confidence: 99%

Interaction of the actin cytoskeleton with microtubules regulates secretory organelle movement near the plasma membrane in human endothelial cells

Manneville¹,

Etienne-Manneville

Skehel

et al. 2003

Journal of Cell Science

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“…42 In addition, it has been shown that cAMP mediates secretion of VWF from peripheral WPBs compared with thrombin/[Ca 2ϩ ]i-mediated release of both central and peripheral VWF granules, suggesting differences in the mechanism of release of WPBs between the 2 pathways. 43 Our findings not only support this mechanistic difference between thrombin/[Ca 2ϩ ]i-and cAMPmediated release of WPB but also suggest that WPBs are heterogeneous in nature and can be differentially regulated.…”

Section: Differential Par and Camp-dependent Exocytosis 2741supporting

confidence: 78%

Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP

Cleator

Zhu

Vaughan

et al. 2006

Blood

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Thrombin-mediated endothelial-cell release of von Willebrand factor (VWF) and P-selectin functionally links proteaseactivated receptors (PARs) to thrombosis and inflammation. VWF release can be stimulated by both Ca 2؉ and cAMP, and, although both VWF and P-selectin are found in Weibel-Palade bodies (WPBs), we found that their release could be differentially regulated. In these studies, human umbilical vein endothelial cells stimulated with cAMP or PAR2-AP led to a delayed release of VWF and significantly less P-selectin release compared with histamine, thrombin, or PAR1-AP. Doseresponse studies revealed that PAR2-AP was significantly less efficacious in promoting the release of P-selectin compared with VWF. PAR2-AP-induced robust stimulation of intracellular Ca 2؉ coupled with a significantly greater inhibitory effect of calcium chelation on release of VWF compared with cell-surface expression of P-selectin, suggests an additional Ca 2؉ -independent pathway involved in release of P-selectin. PAR2-AP failed to increase global cAMP levels; however, inhibition of protein kinase A

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“…Recently, it has been shown that thrombin-induced release of vWF can be potentiated by specific inhibition of Rho, a small GTPase involved in cytoskeletal rearrangements, such as stress fiber formation. 34 This interesting observation suggests that the cytoskeleton may modulate the agonist-induced release of Weibel-Palade bodies. It is possible that Ral-induced changes in the organization of the cytoskeleton may promote fusion of WeibelPalade bodies with the plasma membrane.…”

Section: Discussionmentioning

confidence: 98%

Small GTP-Binding Protein Ral Modulates Regulated Exocytosis of von Willebrand Factor by Endothelial Cells

Leeuw

Fernandez‐Borja

Reits

et al. 2001

ATVB

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Abstract-Weibel-Palade bodies are endothelial cell-specific organelles, which contain von Willebrand factor (vWF), P-selectin, and several other proteins. Recently, we found that the small GTP-binding protein Ral is present in a subcellular fraction containing Weibel-Palade bodies. In the present study, we investigated whether Ral is involved in the regulated exocytosis of Weibel-Palade bodies. Activation of endothelial cells by thrombin resulted in transient cycling of Ral from its inactive GDP-bound to its active GTP-bound state, which coincided with release of vWF. Ral activation and exocytosis of Weibel-Palade bodies were inhibited by incubation with trifluoperazine, an inhibitor of calmodulin, before thrombin stimulation. 3,4 A number of other components have been identified in Weibel-Palade bodies; these include P-selectin, CD63, endothelin, and interleukin-8. [5][6][7][8][9] On stimulation with agonists such as thrombin and histamine, Weibel-Palade bodies release their contents into the blood. 10 -12 The mechanism of thrombin-induced exocytosis of Weibel-Palade bodies has been only partially elucidated. [13][14][15] Thrombin induces the elevation of intracellular Ca 2ϩ levels, which appears crucial for the release of vWF from WeibelPalade bodies. 15,16 Inhibition studies have shown that intracellular Ca 2ϩ exerts its effect on regulated secretion of vWF via calmodulin. 13,15 See coverLittle attention has been directed at involvement of small GTPases in regulated secretion in endothelial cells. Small GTPases cycle between an active GTP-bound and inactive GDP-bound form. Guanine nucleotide exchange factors enhance the conversion from the inactive GDP-bound to the active GTP-bound form, whereas GTPase activating proteins promote the GTP hydrolysis of small GTPases. In many cells, small GTP-binding proteins have been implicated in regulated exocytosis, as exemplified by the pivotal role of Rab3A in the release of synaptic vesicles at the nerve terminal. 17 Therefore, it seems likely that small GTP-binding proteins are also involved in the release of vWF through the regulated pathway in endothelial cells. Recently, we identified the small GTP-binding protein Ral in a subcellular fraction containing Weibel-Palade bodies, suggesting a role for this GTPase in regulated exocytosis of these organelles. 18 Ral is a geranylgeranylated GTPase that is ubiquitously expressed. 19 Activated GTP-bound Ral binds to RLIP76 (or Ral binding protein), an effector molecule that possesses GTPase activity for cdc42 and Rac, suggesting a link between the activation of Ral and rearrangement of the cytoskeleton. 20 Morphological studies have identified Ral on dense granules in platelets and on synaptic vesicles in nerve terminals, suggesting a role for Ral in regulated exocytosis. 21,22 Interestingly, Ral has been proposed to interact with calmodulin in a Ca 2ϩ -dependent manner. 23 Binding to calmodulin enhances GTP binding to Ral 2-to 3-fold. 24 These observations may suggest a regulatory role for Ral in the calmodulin-mediated ...

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Regulated von Willebrand Factor Secretion Is Associated With Agonist-Specific Patterns of Cytoskeletal Remodeling in Cultured Endothelial Cells

Abstract: Abstract-von

Cited by 77 publications

References 30 publications

Interaction of the actin cytoskeleton with microtubules regulates secretory organelle movement near the plasma membrane in human endothelial cells

Interaction of the actin cytoskeleton with microtubules regulates secretory organelle movement near the plasma membrane in human endothelial cells

Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP

Small GTP-Binding Protein Ral Modulates Regulated Exocytosis of von Willebrand Factor by Endothelial Cells

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