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.

1. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, 7301 Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor Michigan 48109-0644, USA.
2. Ludwig Institute for Cancer Research, Stockholm Branch, Karolinska Institutet, PO Box 240, S-171 77 Stockholm, Sweden.
3. Laboratory of Vascular Biology, Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
4. Center for Vascular and Inflammatory Disease and Departments of Surgery and Physiology, University of Maryland School of Medicine, 800 West Baltimore Street, Baltimore, Maryland 21201, USA.
5. Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA.
6. These authors contributed equally to this work.

Correspondence to: Daniel A Lawrence¹ e-mail: dlawrenc@umich.edu

Correspondence to: Ulf Eriksson² e-mail: ulf.eriksson@licr.ki.se

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