Dataset Information

Urokinase-type plasminogen activator promotes N-cadherin-mediated synaptic recovery in the ischemic brain.

ABSTRACT: Urokinase-type plasminogen activator (uPA) is a serine proteinase that catalyzes the generation of plasmin on the cell surface and activates cell signaling pathways that promote remodeling and repair. Neuronal cadherin (NCAD) is a transmembrane protein that in the mature brain mediates the formation of synaptic contacts in the II/III and V cortical layers. Our studies show that uPA is preferentially found in the II/III and V cortical laminae of the gyrencephalic cortex of the non-human primate. Furthermore, we found that in murine cerebral cortical neurons and induced pluripotent stem cell (iPSC)-derived neurons prepared from healthy human donors, most of this uPA is associated with pre-synaptic vesicles. Our in vivo experiments revealed that in both, the gyrencephalic cortex of the non-human primate and the lissecephalic murine brain, cerebral ischemia decreases the number of intact synaptic contacts and the expression of uPA and NCAD in a band of tissue surrounding the necrotic core. Additionally, our in vitro data show that uPA induces the synthesis of NCAD in cerebral cortical neurons, and in line with these observations, intravenous treatment with recombinant uPA three hours after the onset of cerebral ischemia induces NCAD-mediated repair of synaptic contacts in the area surrounding the necrotic core.

SUBMITTER: Diaz A

PROVIDER: S-EPMC8393294 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Urokinase-type plasminogen activator promotes N-cadherin-mediated synaptic recovery in the ischemic brain.

Diaz Ariel A Merino Paola P McCann Patrick P Yepes Manuel A MA Quiceno Laura G LG Torre Enrique E Tomkins Amelia A Zhang Xiaodong X Hales Chadwick M CM Tong Frank C FC Yepes Manuel M

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20210324 9

Urokinase-type plasminogen activator (uPA) is a serine proteinase that catalyzes the generation of plasmin on the cell surface and activates cell signaling pathways that promote remodeling and repair. Neuronal cadherin (NCAD) is a transmembrane protein that in the mature brain mediates the formation of synaptic contacts in the II/III and V cortical layers. Our studies show that uPA is preferentially found in the II/III and V cortical laminae of the gyrencephalic cortex of the non-human primate. ...[more]

PMID: 33757316

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Project description:Data from clinical studies, cell culture, and animal models implicate the urokinase (uPA)/Plasminogen (Plg) system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/Plg stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression to clarify mechanisms of uPA/Plg-accelerated atherosclerosis and aneurysm formation. Microarray studies were performed to identify potential mediators of uPA-accelerated atherosclerosis. These studies identified S100A8 and S100A9 mRNA as the most highly upregulated transcripts in uPA-overexpressing macrophages; upregulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also upregulated in aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is upregulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Bioinformatics analysis of the microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm—in a second animal model—that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease. Six independent biological replicate RNA samples were prepared from thioglycollate-elicited peritoneal macrophages from mice of two different genotypes: SR-uPA+/0 transgenic (overexpress uPA in macrophages) and nontransgenic, respectively), for a total of 12 independent RNA samples. Both transgenic and nontransgenic mice were Apoe-/- and were fed Western diet from 5-15 weeks before peritoneal macrophages were elicited. In addition, from the six samples of each genotype, a pooled sample was prepared by combining the six genotype-specific samples. Each of the two pooled samples was assayed on the BeadChip in two technical replicates, for a total of 16 hybridizations performed using two Illumina Mouse Ref-8 v1.1 chips.

Project description:The last two decades have witnessed a rapid decrease in mortality due to acute cerebral ischemia that paradoxically has led to a rapid increase in the number of patients that survive an acute ischemic stroke with various degrees of disability. Unfortunately, the lack of an effective therapeutic strategy to promote neurological recovery among stroke survivors has led to a rapidly growing population of disabled patients. Thus, understanding the mechanisms of neurorepair in the ischemic brain is a priority with wide scientific, social and economic implications. Cerebral ischemia has a harmful effect on synaptic structure associated with the development of functional impairment. In agreement with these observations, experimental evidence indicates that synaptic repair underlies the recovery of neurological function following an ischemic stroke. Furthermore, it has become evident that synaptic plasticity is crucial not only during development and learning, but also for synaptic repair after an ischemic insult. The plasminogen activating system is assembled by a cascade of enzymes and their inhibitors initially thought to be solely involved in the generation of plasmin. However, recent work has shown that in the brain this system has an important function regulating the development of synaptic plasticity via mechanisms that not always require plasmin generation. Urokinase-type plasminogen activator (uPA) is a serine proteinase and one of the plasminogen activators, that upon binding to its receptor (uPAR) not only catalyzes the conversion of plasminogen into plasmin on the cell surface, but also activates cell signaling pathways that promote cell migration, proliferation and survival. The role of uPA is the brain is not fully understood. However, it has been reported while uPA and uPAR are abundantly found in the developing central nervous system, in the mature brain their expression is restricted to a limited group of cells. Remarkably, following an ischemic injury to the mature brain the expression of uPA and uPAR increases to levels comparable to those observed during development. More specifically, neurons release uPA during the recovery phase from an ischemic injury, and astrocytes, axonal boutons and dendritic spines recruit uPAR to their plasma membrane. Here we will review recent evidence indicating that binding of uPA to uPAR promotes the repair of synapses damaged by an ischemic injury, with the resultant recovery of neurological function. Furthermore, we will discuss data indicating that treatment with recombinant uPA is a potential therapeutic strategy to promote neurological recovery among ischemic stroke survivors.

Dataset Information

Urokinase-type plasminogen activator promotes N-cadherin-mediated synaptic recovery in the ischemic brain.

Publications

Urokinase-type plasminogen activator promotes N-cadherin-mediated synaptic recovery in the ischemic brain.

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