Review Article

The Plasminogen Activation System Promotes Neurorepair in the Ischemic Brain

Author(s): Manuel Yepes*

Volume 20, Issue 9, 2019

Page: [953 - 959] Pages: 7

DOI: 10.2174/1389450120666181211144550

Abstract

The plasminogen activation (PA) system was originally thought to exclusively promote the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases: tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). However, experimental evidence accumulated over the last 30 years indicates that tPA and uPA are also found in the central nervous system (CNS), where they have a plethora of functions that not always require plasmin generation or fibrin degradation. For example, plasminogen-dependent and - independent effects of tPA and uPA play a central role in the pathophysiological events that underlie one of the leading causes of mortality and disability in the world: cerebral ischemia. Indeed, recent work indicates that while the rapid release of tPA from the presynaptic compartment following the onset of cerebral ischemia protects the synapse from the deleterious effects of the ischemic injury, the secretion of uPA and its binding to its receptor (uPAR) during the recovery phase promotes the repair of synapses that have been lost to the acute ischemic insult. This restorative role of uPA has high translational significance because to this date there is no effective approach to induce neurorepair in the ischemic brain. Here we will discuss recent evidence that bridges the gap between basic research in the field of the PA system and the bedside of ischemic stroke patients, indicating that uPA and uPAR are potential targets for the development of therapeutic strategies to promote neurological recovery among ischemic stroke survivors.

Keywords: Tissue-type plasminogen activator, urokinase-type plasminogen activator, plasmin, neurorepair, cerebral ischemia, neuroprotection.

Graphical Abstract
[1]
Pittman RN, Ivins JK, Buettner HM. Neuronal plasminogen activators: cell surface binding sites and involvement in neurite outgrowth. J Neurosci 1989; 9(12): 4269-86.
[2]
Lawrence D, Strandberg L, Grundstrom T, Ny T. Purification of active human plasminogen activator inhibitor 1 from Escherichia coli. Comparison with natural and recombinant forms purified from eucaryotic cells. Eur J Biochem 1989; 186(3): 523-33.
[3]
Yepes M, Sandkvist M, Wong MK, et al. Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood 2000; 96(2): 569-76.
[4]
Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3(12): 932-43.
[5]
Stepanova VV, Tkachuk VA. Urokinase as a multidomain protein and polyfunctional cell regulator. Biochemistry (Mosc) 2002; 67(1): 109-18.
[6]
Yepes M, Roussel BD, Ali C, Vivien D. Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci 2009; 32(1): 48-55.
[7]
Seeds NW, Basham ME, Haffke SP. Neuronal migration is retarded in mice lacking the tissue plasminogen activator gene. Proc Natl Acad Sci USA 1999; 96(24): 14118-23.
[8]
Lee SH, Ko HM, Kwon KJ, et al. tPA regulates neurite outgrowth by phosphorylation of LRP5/6 in neural progenitor cells. Mol Neurobiol 2014; 49(1): 199-215.
[9]
Qian Z, Gilbert ME, Colicos MA, Kandel ER, Kuhl D. Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nat 1993; 361(6411): 453-7.
[10]
Seeds NW, Basham ME, Ferguson JE. Absence of tissue plasminogen activator gene or activity impairs mouse cerebellar motor learning. J Neurosci 2003; 23(19): 7368-75.
[11]
Seeds NW, Williams BL, Bickford PC. Tissue plasminogen activator induction in Purkinje neurons after cerebellar motor learning. Sci 1995; 270(5244): 1992-4.
[12]
Pawlak R, Magarinos AM, Melchor J, McEwen B, Strickland S. Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior. Nat Neurosci 2003; 6(2): 168-74.
[13]
Echeverry R, Wu J, Haile WB, Guzman J, Yepes M. Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus. J Clin Invest 2010; 120(6): 2194-205.
[14]
Yepes M, Sandkvist M, Moore EG, Bugge TH, Strickland DK, Lawrence DA. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest 2003; 112(10): 1533-40.
[15]
Polavarapu R, Jie A, Zhang CH, Yepes M. Regulated intramembranous proteolysis of the low density lipoprotein receptor-related protein mediates ischemic cell death. Am J Pathol 2008: In Press
[16]
Adams HP Jr, Adams RJ, Brott T, et al. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Stroke Association. Stroke 2003; 34(4): 1056-83.
[17]
Baron A, Montagne A, Casse F, et al. NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity. Cell Death Differ 2010; 17(5): 860-71.
[18]
Higgins DL, Vehar GA. Interaction of one-chain and two-chain tissue plasminogen activator with intact and plasmin-degraded fibrin. Biochem 1987; 26(24): 7786-91.
[19]
Sappino AP, Madani R, Huarte J, et al. Extracellular proteolysis in the adult murine brain. J Clin Invest 1993; 92(2): 679-85.
[20]
Vassalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991; 88(4): 1067-72.
[21]
Park L, Gallo EF, Anrather J, et al. Key role of tissue plasminogen activator in neurovascular coupling. Proc Natl Acad Sci USA 2008; 105(3): 1073-8.
[22]
Wang YF, Tsirka SE, Strickland S, et al. Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med 1998; 4(2): 228-31.
[23]
Sashindranath M, Sales E, Daglas M, et al. The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans. Brain 2012; 135(Pt 11): 3251-64.
[24]
Nicole O, Docagne F, Ali C, et al. The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nat Med 2001; 7(1): 59-64.
[25]
Jeanneret V, Wu F, Merino P, et al. Tissue-type plasminogen activator (tpa) modulates the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate. Front Mol Neurosci 2016; 9: 121.
[26]
Wu F, Nicholson AD, Haile WB, et al. Tissue-type plasminogen activator mediates neuronal detection and adaptation to metabolic stress. J Cereb Blood Flow Metab 2013; 33(11): 1761-9.
[27]
Wu F, Wu J, Nicholson AD, et al. Tissue-type plasminogen activator regulates the neuronal uptake of glucose in the ischemic brain. J Neurosci 2012; 32(29): 9848-58.
[28]
Liu Z, Li Y, Zhang L, et al. Subacute intranasal administration of tissue plasminogen activator increases functional recovery and axonal remodeling after stroke in rats. Neurobiol Dis 2012; 45(2): 804-9.
[29]
Larsson LI, Skriver L, Nielsen LS, et al. Distribution of urokinase-type plasminogen activator immunoreactivity in the mouse. J Cell Biol 1984; 98(3): 894-903.
[30]
Lijnen HR, Van Hoef B, Collen D. Activation with plasmin of tow-chain urokinase-type plasminogen activator derived from single-chain urokinase-type plasminogen activator by treatment with thrombin Eur J Biochem / FEBS 1987; 169(2): 359-64.
[31]
Andreasen PA, Kjoller L, Christensen L, Duffy MJ. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997; 72(1): 1-22.
[32]
Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 2004; 10(1): 39-49.
[33]
Rabbani SA, Mazar AP, Bernier SM, et al. Structural requirements for the growth factor activity of the amino-terminal domain of urokinase. J Biol Chem 1992; 267(20): 14151-6.
[34]
Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 2010; 11(1): 23-36.
[35]
Sumi Y, Dent MA, Owen DE, Seeley PJ, Morris RJ. The expression of tissue and urokinase-type plasminogen activators in neural development suggests different modes of proteolytic involvement in neuronal growth. Development 1992; 116(3): 625-37.
[36]
Dent MA, Sumi Y, Morris RJ, Seeley PJ. Urokinase-type plasminogen activator expression by neurons and oligodendrocytes during process outgrowth in developing rat brain. Eur J Neurosci 1993; 5(6): 633-47.
[37]
Masos T, Miskin R. Localization of urokinase-type plasminogen activator mRNA in the adult mouse brain. Mol Brain Res 1996; 35(1-2): 139-48.
[38]
Yamamoto M, Sawaya R, Mohanam S, et al. Expression and localization of urokinase-type plasminogen activator in human astrocytomas in vivo. Cancer Res 1994; 54(14): 3656-61.
[39]
Yamamoto M, Sawaya R, Mohanam S, et al. Expression and localization of urokinase-type plasminogen activator receptor in human gliomas. Cancer Res 1994; 54(18): 5016-20.
[40]
Merino P, Diaz A, Jeanneret V, et al. Urokinase-type Plasminogen Activator (uPA) Binding to the uPA Receptor (uPAR) Promotes Axonal Regeneration in the Central Nervous System. J Biol Chem 2017; 292(7): 2741-53.
[41]
Wu F, Catano M, Echeverry R, et al. Urokinase-type plasminogen activator promotes dendritic spine recovery and improves neurological outcome following ischemic stroke. J Neurosci 2014; 34(43): 14219-32.
[42]
del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke 1998; 29(1): 4-11.
[43]
Le Bihan D. Looking into the functional architecture of the brain with diffusion MRI. Nat Rev Neurosci 2003; 4(6): 469-80.
[44]
Dijkhuizen RM, Ren J, Mandeville JB, et al. Functional magnetic resonance imaging of reorganization in rat brain after stroke. Proc Natl Acad Sci USA 2001; 98(22): 12766-71.
[45]
Murphy TH, Corbett D. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci 2009; 10(12): 861-72.
[46]
Hasbani MJ, Underhill SM, Erausquin G, Goldberg MP. Synapse loss and regeneration: a mechanism for functional decline and recovery after cerebral ischemia? The Neuroscientist 2000; 6(2)
[47]
Hinman JD. The back and forth of axonal injury and repair after stroke. Curr Opin Neurol 2014; 27(6): 615-23.
[48]
Torre ER, Gutekunst CA, Gross RE. Expression by midbrain dopamine neurons of Sema3A and 3F receptors is associated with chemorepulsion in vitro but a mild in vivo phenotype. Mol Cell Neurosci 2010; 44(2): 135-53.
[49]
He Z, Jin Y. Intrinsic control of axon regeneration. Neuron 2016; 90(3): 437-51.
[50]
Liu K, Tedeschi A, Park KK, He Z. Neuronal intrinsic mechanisms of axon regeneration. Annu Rev Neurosci 2011; 34: 131-52.
[51]
Fries W, Danek A, Scheidtmann K, Hamburger C. Motor recovery following capsular stroke. Role of descending pathways from multiple motor areas. Brain 1993; 116(Pt 2): 369-82.
[52]
Connolly BM, Choi EY, Gardsvoll H, et al. Selective abrogation of the uPA-uPAR interaction in vivo reveals a novel role in suppression of fibrin-associated inflammation. Blood 2010; 116(9): 1593-603.
[53]
Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H. Structure-stability-function relationships of dendritic spines. Trends Neurosci 2003; 26(7): 360-8.
[54]
Zhang S, Boyd J, Delaney K, Murphy TH. Rapid reversible changes in dendritic spine structure in vivo gated by the degree of ischemia. J Neurosci 2005; 25(22): 5333-8.
[55]
Hotulainen P, Hoogenraad CC. Actin in dendritic spines: connecting dynamics to function. J Cell Biol 2010; 189(4): 619-29.
[56]
Hotulainen P, Paunola E, Vartiainen MK, Lappalainen P. Actin-depolymerizing factor and cofilin-1 play overlapping roles in promoting rapid F-actin depolymerization in mammalian nonmuscle cells. Mol Biol Cell 2005; 16(2): 649-64.
[57]
Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 2002; 3(8): 586-99.
[58]
Fehon RG, McClatchey AI, Bretscher A. Organizing the cell cortex: the role of ERM proteins. Nat Rev Mol Cell Biol 2010; 11(4): 276-87.
[59]
Merino P, Diaz A, Manrique LG, Cheng L, Yepes M. Urokinase-type plasminogen activator (uPA) promotes ezrin-mediated reorganization of the synaptic cytoskeleton in the ischemic brain. J Biol Chem 2018; 293(24): 9234-47.
[60]
Diaz A, Merino P, Manrique LG, et al. A Cross-talk between neuronal urokinase-type plasminogen activator (upa) and astrocytic upa receptor (upar) promotes astrocytic activation and synaptic recovery in the ischemic brain. J Neurosci 2017; 37(43): 10310-22.
[61]
Li L, Lundkvist A, Andersson D, et al. Protective role of reactive astrocytes in brain ischemia. J Cereb Blood Flow Metab 2008; 28(3): 468-81.
[62]
Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci 2004; 5(2): 146-56.
[63]
Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 2009; 32(8): 421-31.
[64]
Ventura R, Harris KM. Three-dimensional relationships between hippocampal synapses and astrocytes. J Neurosci 1999; 19(16): 6897-906.
[65]
Diaz A, Yepes M. Urokinase-type plasminogen activator promotes synaptic repair in the ischemic brain. Neural Regen Res 2018; 13(2): 232-3.

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