Plasminogen Activators in Ischemic Stroke

Schielke, Gerald P.; Lawrence, Daniel A.

doi:10.1002/9783527649327.ch6

Cited by 3 publications

(4 citation statements)

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“… 22 , 25 Multiple potential substrates and receptors for tPA have also been proposed to mediate these diverse effects, including plasminogen, NMDA receptors, LRP1, and PDGF-CC. 1 – 3 However, it is possible that the neurovascular events regulated by tPA and neuroserpin described here could provide a unifying pathway for many of the pleotropic effects of tPA. For example, studies have suggested that a primary role of tPA in the CNS is direct regulation of neuronal activity through its action on the NMDA receptor and neuronal calcium signaling.…”

Section: Discussionmentioning

confidence: 98%

“…The role of tPA in the CNS has been controversial. 1 – 3 , 66 It has been proposed that tPA directly affects multiple physiologic processes, such as neuronal development, 67 neuronal plasticity, 68 axonal regeneration, 69 , 70 as well as multiple pathologic processes, such as excitotoxicity, 71 microglial activation/inflammation, 72 , 73 and BBB dysfunction. 22 , 25 Multiple potential substrates and receptors for tPA have also been proposed to mediate these diverse effects, including plasminogen, NMDA receptors, LRP1, and PDGF-CC.…”

Section: Discussionmentioning

confidence: 99%

“…The serine protease tissue-type plasminogen activator (tPA) is primarily known for its thrombolytic activity; however, within the central nervous system (CNS) tPA is reported to have pleiotropic effects, regulating events such as neuronal plasticity, neurovascular coupling, and neurovascular barrier control (reviewed in 1 – 3 ). In vitro studies have demonstrated that tPA activity can be regulated by neuroserpin, 4 , 5 a member of the ser ine p rotease in hibitor (serpin) family 4 , 6 that is primarily expressed in the brain.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a neurovascular signaling pathway regulating seizures in mice

Fredriksson

Stevenson

et al. 2015

Ann Clin Transl Neurol

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ObjectiveA growing body of evidence suggests that increased blood–brain barrier (BBB) permeability can contribute to the development of seizures. The protease tissue plasminogen activator (tPA) has been shown to promote BBB permeability and susceptibility to seizures. In this study, we examined the pathway regulated by tPA in seizures.MethodsAn experimental model of kainate-induced seizures was used in genetically modified mice, including mice deficient in tPA (tPA−/−), its inhibitor neuroserpin (Nsp−/−), or both (Nsp:tPA−/−), and in mice conditionally deficient in the platelet-derived growth factor receptor alpha (PDGFRα).ResultsCompared to wild-type (WT) mice, Nsp−/− mice have significantly reduced latency to seizure onset and generalization; whereas tPA−/− mice have the opposite phenotype, as do Nsp:tPA−/− mice. Furthermore, interventions that maintain BBB integrity delay seizure propagation, whereas osmotic disruption of the BBB in seizure-resistant tPA−/− mice dramatically reduces the time to seizure onset and accelerates seizure progression. The phenotypic differences in seizure progression between WT, tPA−/−, and Nsp−/− mice are also observed in electroencephalogram recordings in vivo, but absent in ex vivo electrophysiological recordings where regulation of the BBB is no longer necessary to maintain the extracellular environment. Finally, we demonstrate that these effects on seizure progression are mediated through signaling by PDGFRα on perivascular astrocytes.InterpretationTogether, these data identify a specific molecular pathway involving tPA-mediated PDGFRα signaling in perivascular astrocytes that regulates seizure progression through control of the BBB. Inhibition of PDGFRα signaling and maintenance of BBB integrity might therefore offer a novel clinical approach for managing seizures.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of a neurovascular signaling pathway regulating seizures in mice

Fredriksson

Stevenson

et al. 2015

Ann Clin Transl Neurol

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“…The role of tPA within the central nervous system (CNS) is controversial (Su et al, 2009 ; Yepes et al, 2009 ; Lemarchant et al, 2012 ; Schielke and Lawrence, 2012 ). It has been proposed that tPA directly affects multiple processes, including neuronal development/plasticity/excitotoxicity (Tsirka et al, 1996 ; Seeds et al, 2003 ; Li et al, 2013 ), microglial activation (Tsirka et al, 1997 ; Rogove and Tsirka, 1998 ), as well as regulation of cerebrovascular permeability (Yepes et al, 2003 ; Su et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

tPA Deficiency in Mice Leads to Rearrangement in the Cerebrovascular Tree and Cerebroventricular Malformations

Stefanitsch

Lawrence

Olverling

et al. 2015

Front. Cell. Neurosci.

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The serine protease tissue-type plasminogen activator (tPA) is used as a thrombolytic agent in the management of ischemic stroke, but concerns for hemorrhagic conversion greatly limits the number of patients that receive this treatment. It has been suggested that the bleeding complications associated with thrombolytic tPA may be due to unanticipated roles of tPA in the brain. Recent work has suggested tPA regulation of neurovascular barrier integrity, mediated via platelet derived growth factor (PDGF)-C/PDGF receptor-α (PDGFRα) signaling, as a possible molecular mechanism affecting the outcome of stroke. To better understand the role of tPA in neurovascular regulation we conducted a detailed analysis of the cerebrovasculature in brains from adult tPA deficient (tPA−/−) mice. Our analysis demonstrates that life-long deficiency of tPA is associated with rearrangements in the cerebrovascular tree, including a reduction in the number of vascular smooth-muscle cell covered, large diameter, vessels and a decrease in vessel-associated PDGFRα expression as compared to wild-type (WT) littermate controls. In addition, we found that ablation of tPA results in an increased number of ERG-positive endothelial cells and increased junctional localization of the tight junction protein ZO1. This is intriguing since ERG is an endothelial transcription factor implicated in regulation of vascular integrity. Based on these results, we propose that the protection of barrier properties seen utilizing these tPA−/− mice might be due, at least in part, to these cerebrovascular rearrangements. In addition, we found that tPA−/− mice displayed mild cerebral ventricular malformations, a feature previously associated with ablation of PDGF-C, thereby providing an in vivo link between tPA and PDGF signaling in central nervous system (CNS) development. Taken together, the data presented here will advance our understanding of the role of tPA within the CNS and in regulation of cerebrovascular permeability.

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What drives “fibrinolysis”?

Medcalf¹

2015

Hamostaseologie

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The timely removal of blood clots and fibrin deposits is essential in the regulation of haemostasis. This is achieved by the fibrinolytic system, an enzymatic process that regulates the activation of plasminogen into its proteolytic form, plasmin. This is a self-regulated event as the very presence of fibrin initiates plasminogen activation on the fibrin surface due to the presentation of exposed C-terminal lysine residues in fibrin that allow plasminogen to position itself via its lysine binding sites and to be more efficiently cleaved by tissue-type plasminogen activator (t-PA). Hence fibrin, the ultimate substrate of plasmin during fibrinolysis, is indeed an essential cofactor in the cascade. What has now come to light is that the fibrinolytic system is not solely designed to eliminate fibrin. Indeed, it is a broad acting system that processes a variety of proteins, including many in the brain where there is no fibrin. So what drives t-PA-mediated plasminogen activation when fibrin is not available? This review will describe the broadening role of the fibrinolytic system highlighting the importance of fibrin and other key proteins as facilitators during t-PA-mediated plasminogen activation.

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Plasminogen Activators in Ischemic Stroke

Cited by 3 publications

References 174 publications

Identification of a neurovascular signaling pathway regulating seizures in mice

Identification of a neurovascular signaling pathway regulating seizures in mice

tPA Deficiency in Mice Leads to Rearrangement in the Cerebrovascular Tree and Cerebroventricular Malformations

What drives “fibrinolysis”?

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