Storage and Release of Tissue Plasminogen Activator by Sympathetic Axons in Resistance Vessel Walls

Jiang, Xi; Hand, Arthur R.; Gillies, Concettina; Cone, Robert E.; Kirk, J. R. Van; O’Rourke, James

doi:10.1006/mvre.2002.2441

Cited by 29 publications

(38 citation statements)

References 30 publications

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“…Likewise, this process may also play a role in vascular permeability outside of the CNS, since tPA antigen has been observed in the sympathetic axons innervating the smooth muscle in the walls of peripheral vessels (47), which are also know to express significant levels of LRP (30,48). Thus, our results imply a new Plg-independent role for tPA as a potent but previously unrecognized regulator of vascular permeability.…”

Section: Discussionsupporting

confidence: 55%

Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor–related protein

Yepes¹,

Sandkvist²,

Moore³

et al. 2003

J. Clin. Invest.

298

381

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Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: tissue-type plasminogen activator (tPA); plasminogen (Plg); middle cerebral artery occlusion (MCAO); blood-brain barrier (BBB); LDL receptor-related protein (LRP); urokinase-type plasminogen activator (uPA); receptor-associated protein (RAP); N-methyl-Daspartate (NMDA); protease-activated receptor (PAR).

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Section: Discussionsupporting

confidence: 55%

Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor–related protein

Yepes¹,

Sandkvist²,

Moore³

et al. 2003

J. Clin. Invest.

298

381

View full text Add to dashboard Cite

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“…Hence, these results may suggest an important system and mechanism for the regulation of neurosecretory and catecholaminergic pathways in both central and peripheral nervous systems, with implications, for example, for t-PA/ plasminogen-dependent processes such as long-term potentiation, learning, and memory (Qian et al, 1993;Carmeliet et al, 1994;Frey et al, 1996;Huang et al, 1996;Baranes et al, 1998;Seeds et al, 2003;Pang et al, 2004), and excitotoxin-induced neuronal injury in the CNS (Tsirka et al, , 1997aChenLiu and Strickland, 1997), as well as for the regulation of key systemic cardiovascular and metabolic homeostatic physiological responses governed by sympathoadrenal and sympathoneural activity (Parmer et al, 2000;Jiang et al, 2001;Q. Jiang et al, 2002;X. Jiang et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Cell-Surface Actin Binds Plasminogen and Modulates Neurotransmitter Release from Catecholaminergic Cells

Miles¹,

Andronicos²,

Baik³

et al. 2006

J. Neurosci.

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An emerging area of research has documented a novel role for the plasminogen activation system in the regulation of neurotransmitter release. Prohormones, secreted by cells within the sympathoadrenal system, are processed by plasmin to bioactive peptides that feed back to inhibit secretagogue-stimulated release. Catecholaminergic cells of the sympathoadrenal system are prototypic prohormone-secreting cells. Processing of prohormones by plasmin is enhanced in the presence of catecholaminergic cells, and the enhancement requires binding of plasmin(ogen) to cellular receptors. Consequently, modulation of the local cellular fibrinolytic system of catecholaminergic cells results in substantial changes in catecholamine release. However, mechanisms for enhancing prohormone processing and cellsurface molecules mediating the enhancement on catecholaminergic cells have not been investigated. Here we show that plasminogen activation was enhanced Ͼ6.5-fold on catecholaminergic cells. Carboxypeptidase B treatment decreased cell-dependent plasminogen activation by ϳ90%, suggesting that the binding of plasminogen to proteins exposing C-terminal lysines on the cell surface is required to promote plasminogen activation. We identified catecholaminergic plasminogen receptors required for enhancing plasminogen activation, using a novel strategy combining targeted specific proteolysis using carboxypeptidase B with a proteomics approach using twodimensional gel electrophoresis, radioligand blotting, and tandem mass spectrometry. Two major plasminogen-binding proteins that exposed C-terminal lysines on the cell surface contained amino acid sequences corresponding to ␤/␥-actin. An anti-actin monoclonal antibody inhibited cell-dependent plasminogen activation and also enhanced nicotine-dependent catecholamine release. Our results suggest that cell-surface-expressed forms of actin bind plasminogen, thereby promoting plasminogen activation and increased prohormone processing leading to inhibition of neurotransmitter release.

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“…One possibility is that t-PA released from the sympathetic terminals system itself contributes to the observed response. O'Rourke and co-workers have shown that sympathetic neurons can synthesise and release t-PA [162,163]. However, whether t-PA derived from sympathetic neurons actually reaches the blood stream remains to be determined.…”

Section: Effects Of Tachycardia and Hyperaemia On Coronary T-pa Releamentioning

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

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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.

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Storage and Release of Tissue Plasminogen Activator by Sympathetic Axons in Resistance Vessel Walls

Cited by 29 publications

References 30 publications

Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor–related protein

Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor–related protein

Cell-Surface Actin Binds Plasminogen and Modulates Neurotransmitter Release from Catecholaminergic Cells

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

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