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Article
Nature Medicine 14, 731 - 737 (2008)
Published online: 22 June 2008 | doi:10.1038/nm1787
Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke
Enming J Su1, Linda Fredriksson2, Melissa Geyer1,6, Erika Folestad2,6, Jacqueline Cale1, Johanna Andrae2,3, Yamei Gao4, Kristian Pietras2, Kris Mann1, Manuel Yepes5, Dudley K Strickland4, Christer Betsholtz3, Ulf Eriksson2 & Daniel A Lawrence1
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-
receptors (PDGFR-) on perivascular astrocytes, and treatment of mice with the PDGFR- 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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