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Author Notes:

Email Address: myepes@emory.edu

F.C.T. and M.Y. designed research; F.W., M.C., R.E., E.T., W.B.H., J.A., C.C., L.C., A.N., and J.P. performed research.

F.C.T. contributed unpublished reagents/analytic tools; F.C.T. and M.Y. analyzed data; M.Y. wrote the paper.

The authors declare no competing financial interests.


Research Funding:

This work has been supported in part by National Institutes of Health Grants NS-062073 (to M.Y.) and NS-079331 (to M.Y.) and VA Merit Award BX000474 (to M.Y.).


  • cerebral ischemia
  • recovery
  • stroke
  • urokinase-type plasminogen activator

Urokinase-Type Plasminogen Activator Promotes Dendritic Spine Recovery and Improves Neurological Outcome Following Ischemic Stroke

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Journal Title:

Journal of Neuroscience Nursing


Volume 34, Number 43


, Pages 14219-14232

Type of Work:

Article | Final Publisher PDF


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.

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© 2014 the authors

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