title: Urokinase-type plasminogen activator promotes dendritic spine recovery and improves neurological outcome following ischemic stroke.
abstract: Spines are dendritic protrusions that receive most of the excitatory input in the brain. Early after the onset of cerebral ischemia dendritic spines in the peri-infarct cortex are replaced by areas of focal swelling, and their re-emergence from these varicosities is associated with neurological recovery after acute ischemic stroke (AIS). Urokinase-type plasminogen activator (uPA) is a serine proteinase that plays a central role in tissue remodeling via binding to the urokinase plasminogen activator receptor (uPAR). We report that cerebral cortical neurons release uPA during the recovery phase from ischemic stroke in vivo or hypoxia in vitro. Although uPA does not have an effect on ischemia- or hypoxia-induced neuronal death, genetic deficiency of uPA (uPA(-/-)) or uPAR (uPAR(-/-)) abrogates functional recovery after AIS. Treatment with recombinant uPA after ischemic stroke induces neurological recovery in wild-type and uPA(-/-) but not in uPAR(-/-) mice. Diffusion tensor imaging studies indicate that uPA(-/-) mice have increased water diffusivity and decreased anisotropy associated with impaired dendritic spine recovery and decreased length of distal neurites in the peri-infarct cortex. We found that the excitotoxic injury induces the clustering of uPAR in dendritic varicosities, and that the binding of uPA to uPAR promotes the reorganization of the actin cytoskeleton and re-emergence of dendritic filopodia from uPAR-enriched varicosities. This effect is independent of uPA's proteolytic properties and instead is mediated by Rac-regulated profilin expression and cofilin phosphorylation. Our data indicate that binding of uPA to uPAR promotes dendritic spine recovery and improves functional outcome following AIS.
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Marcela
authors.initials: M
authors.lastname: Catano
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Echeverry
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Enrique
authors.initials: E
authors.lastname: Torre
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Woldeab B
authors.initials: WB
authors.lastname: Haile
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, Department of Pharmacology, Shandong University School of Medicine, 250100 Jinan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: An
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Changhua
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Lihong
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Radiology and Imaging Sciences and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Nicholson
authors.affiliation: Departments of Radiology and Neurosurgery, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Tong
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University, Atlanta, Georgia 30322, and.
authors.forename: Jaekeun
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, Department of Neurology, Veterans Affairs Medical Center, Atlanta, Georgia 30349 myepes@emory.edu.
authors.forename: Manuel
authors.identifier: http://orcid.org/0000-0002-5224-9663
authors.initials: M
authors.lastname: Yepes
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009422:Nervous System Diseases / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D016896:Treatment Outcome; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator
keywords: cerebral ischemia; recovery; stroke; urokinase-type plasminogen activator