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      Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke.

      Nature medicine
      Animals, Benzamides, Blood-Brain Barrier, pathology, Brain, blood supply, ultrastructure, Brain Ischemia, metabolism, Fibrinolytic Agents, Lymphokines, Mice, Mice, Inbred C57BL, Piperazines, pharmacology, Platelet-Derived Growth Factor, Pyrimidines, Receptor, Platelet-Derived Growth Factor alpha, antagonists & inhibitors, Stroke, drug therapy, Tissue Plasminogen Activator

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          Abstract

          Thrombolytic treatment of ischemic stroke with tissue plasminogen activator (tPA) is markedly limited owing to concerns about hemorrhagic complications and the requirement that tPA be administered within 3 h of symptoms. Here we report that tPA activation of latent platelet-derived growth factor-CC (PDGF-CC) may explain these limitations. Intraventricular injection of tPA or active PDGF-CC, in the absence of ischemia, leads to significant increases in cerebrovascular permeability. In contrast, co-injection of neutralizing antibodies to PDGF-CC with tPA blocks this increased permeability, indicating that PDGF-CC is a downstream substrate of tPA within the neurovascular unit. These effects are mediated through activation of PDGF-alpha receptors (PDGFR-alpha) on perivascular astrocytes, and treatment of mice with the PDGFR-alpha antagonist imatinib after ischemic stroke reduces both cerebrovascular permeability and hemorrhagic complications associated with late administration of thrombolytic tPA. These data demonstrate that PDGF signaling regulates blood-brain barrier permeability and suggest potential new strategies for stroke treatment.

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