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

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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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Figure 1: Active PDGF-CC mediates tPA-induced cerebrovascular permeability.
Figure 2: tPA and PDGF-CC induce similar morphological changes in brain vasculature.
Figure 3: PDGF-CC, tPA and the PDGFR-α are expressed in the neurovascular unit.
Figure 4: PDGF-CC is expressed by astrocytes in culture.
Figure 5: Blocking PDGFR-α activation reduces cerebrovascular permeability and stroke volume after MCAO.
Figure 6: Blocking the PDGF-CC–PDGFR-α pathway reduces intracerebral hemorrhage after MCAO.


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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.).

Author information

E.J.S. and L.F. conceived, designed and performed the research and wrote the paper, M.G., E.F., J.C., J.A., Y.G., K.P. and K.M. performed the research, M.Y. conceived the research, D.K.S. and C.B. designed the research and contributed vital reagents, U.E. and D.A.L. conceived and designed the research and wrote the paper.

Correspondence to Ulf Eriksson or Daniel A Lawrence.

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Su, E., Fredriksson, L., Geyer, M. et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat Med 14, 731–737 (2008) doi:10.1038/nm1787

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