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-α receptors (PDGFR-α) on perivascular astrocytes, and treatment of mice with the PDGFR-α 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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We want to thank P. Soriano (Fred Hutchinson Cancer Research Center) for the PDGFR-α–GFP mice; A. Nagy (Samuel Lunenfeld Research Institute, Mount Sinai Hospital) for the PDGF-C–knockout mice; M. Wang, G. Schielke and D. Lombardi for helpful discussions and critical reading of the manuscript; N. Gorlatova for surface plasmon resonance analysis; and S. Rezaian and M. Wahl for technical assistance. This work was supported by National Institutes of Health grants HL55374, HL55747, HL54710 and HL57346 (to D.A.L.); HL50784 and HL54710 (to D.K.S.); NS49478 (to M.Y.); and grants from Karolinska Institutet, Novo Nordisk Foundation, Swedish Research Council, Swedish Cancer Foundation, the LeDucq Foundation and IngaBritt and Arne Lundberg Foundation (to U.E. and C.B.).
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