Tissue-type plasminogen activator (t-PA) is stored in Weibel-Palade bodies in human endothelial cells both in vitro and in vivo

Huber, Denise; Cramer, Elisabeth M.; Kaufmann, J. E.; Meda, Paolo; Massé, Jean‐Marc; Kruithof, Egbert K. O.; Vischer, Ulrich M.

doi:10.1182/blood.v99.10.3637

Cited by 116 publications

(89 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By constitutive secretion, the newly synthesised protein continuously leaves the Golgi compartment in transport vesicles that fuse with the cell membrane. By regulated secretion, on the other hand, t-PA is released from small dense vesicles and/or the Weibel-Palade bodies [38][39][40]. The intracellular storage pool of t-PA is quite large, and it follows that the regulated pathway allows local intravascular t-PA concentrations to increase rapidly and substantially [41,42].…”

Section: Regulation Of Intravascular Fibrinolysis In Vivomentioning

confidence: 99%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

View full text Add to dashboard Cite

The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (t-PA) released from endothelial cells. In man, sympathomimetic drugs increase the systemic concentration of t-PA. It is therefore of interest to investigate whether cardiac sympathetic activation can induce a local t-PA release, which could counteract intra-coronary clot formation.Thrombolytic therapy with recombinant t-PA (rt-PA) is effective in acute myocardial infarction, but the treatment is limited by a fairly slow reperfusion rate and frequent early reocclusions. A potential mechanism behind early reocclusions might be that active thrombin is released from the thrombus during thrombolytic therapy. Thrombin has recently been shown to activate procarboxypeptidase U, which in its active form (CPU) down-regulates endogenous fibrinolysis. Therefore, one way of improving thrombolytic efficacy may be to combine rt-PA with a lowmolecular weight direct thrombin inhibitor, which theoretically could have a pro-fibrinolytic effect, either by inhibition of fibrin-bound thrombin and/or by inhibition of CPU activation. An alternative way may be direct inhibition of CPU.In a porcine model, experimental activation of cardiac sympathetic nerves by electrical stimulation at 1 and 8 Hz induced 5-and 20-fold increase in the release of both total and active t-PA together with frequency-dependent increases in heart rate, blood pressure, and coronary blood flow. The t-PA release was independent of the heart rate and coronary flow response, but local infusion of isoprenaline suggested that part of the t-PA response was mediated by stimulation of β-adrenergic receptors. Next, we studied the combined effect of rt-PA and thrombin inhibitors (melagatran, hirudin and heparin) in a canine model of copper coil-induced coronary thrombosis. The profibrinolytic effect of rt-PA, either measured as patency rate or time-to-patency, was significantly enhanced with the low-molecular weight direct thrombin inhibitor melagatran, but to a lesser degree by hirudin and heparin. In the same model it was shown that active CPU is produced locally in the coronary vascular bed during both thrombus formation and clot lysis. Inhibition of thrombin attenuated CPU formation and improved patency. A similar effect was obtained with a direct inhibitor of CPU.In conclusion, the coronary t-PA response to sympathetic stimulation may constitute a thromboprotective defence mechanism to counteract its prothrombotic effects on the systemic level. Furthermore, direct thrombin and/or CPU inhibition may be potential targets for prevention of thrombus formation via facilitation of the endogenous fibrinolytic system.

show abstract

Section: Regulation Of Intravascular Fibrinolysis In Vivomentioning

confidence: 99%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

View full text Add to dashboard Cite

show abstract

“…38 However, this observation is controversial because other studies have shown that t-PA is stored in WPBs in HUVECs. [39][40][41] Indeed, some of the observed differences in localization of t-PA have been ascribed to subtle differences in tissue culture methods. 39 Accordingly, we examined the localization of VWF and P-selectin in our cell-culture system by performing immunostaining and confocal microscopy.…”

Section: Selective Release Of Weibel-palade Bodies That Contain Predomentioning

confidence: 99%

“…[39][40][41] Indeed, some of the observed differences in localization of t-PA have been ascribed to subtle differences in tissue culture methods. 39 Accordingly, we examined the localization of VWF and P-selectin in our cell-culture system by performing immunostaining and confocal microscopy. The majority of P-selectin is localized with VWF in the characteristic WPBs in HUVECs; however, some granules appear to be composed of primarily P-selectin ( Figure 6, see red line).…”

Section: Selective Release Of Weibel-palade Bodies That Contain Predomentioning

confidence: 99%

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

View full text Add to dashboard Cite

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

show abstract

“…P-selectin is stored in Weibel-Palade bodies, endothelial storage granules that also contain von Willebrand factor (VWF) and tissue plasminogen activator (17)(18)(19)(20)(21)(22)(23)(24). Rapid exocytosis of WeibelPalade bodies is activated by thrombin, histamine, and other agonists.…”

mentioning

confidence: 99%

Sphingosine 1-phosphate activates Weibel-Palade body exocytosis

Matsushita

Morrell

Lowenstein

2004

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Sphingosine 1-phosphate (S1P) not only regulates angiogenesis, vascular permeability and vascular tone, but it also promotes vascular inflammation. However, the molecular basis for the proinflammatory effects of S1P is not understood. We now show that S1P activates endothelial cell exocytosis of Weibel-Palade bodies, releasing vasoactive substances capable of causing vascular thrombosis and inflammation. S1P triggers endothelial exocytosis in part through phospholipase C-␥ signal transduction. However, S1P also modulates endothelial cell exocytosis by activating endothelial nitric oxide synthase production of nitric oxide, which inhibits exocytosis. Thus S1P plays a dual role in regulating endothelial exocytosis, triggering pathways that both promote and inhibit endothelial exocytosis. Regulation of endothelial exocytosis may explain part of the proinflammatory effects of S1P.nitric oxide ͉ ceramide ͉ endothelial ͉ von Willebrand factor

show abstract

Tissue-type plasminogen activator (t-PA) is stored in Weibel-Palade bodies in human endothelial cells both in vitro and in vivo

Cited by 116 publications

References 28 publications

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

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

Sphingosine 1-phosphate activates Weibel-Palade body exocytosis

Contact Info

Product

Resources

About