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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Authors | Enming J Su, Linda Fredriksson, Melissa Geyer, Erika Folestad, Jacqueline Cale, Johanna Andrae, Yamei Gao, Kristian Pietras, Kris Mann, Manuel Yepes, Dudley K Strickland, Christer Betsholtz, Ulf Eriksson, Daniel A Lawrence |
Journal | Nature medicine
(Nat Med)
Vol. 14
Issue 7
Pg. 731-7
(Jul 2008)
ISSN: 1546-170X [Electronic] United States |
PMID | 18568034
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Benzamides
- Fibrinolytic Agents
- Lymphokines
- Piperazines
- Platelet-Derived Growth Factor
- Pyrimidines
- platelet-derived growth factor C
- Imatinib Mesylate
- Receptor, Platelet-Derived Growth Factor alpha
- Tissue Plasminogen Activator
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Topics |
- Animals
- Benzamides
- Blood-Brain Barrier
(pathology)
- Brain
(blood supply, ultrastructure)
- Brain Ischemia
(metabolism, pathology)
- Fibrinolytic Agents
(metabolism)
- Imatinib Mesylate
- Lymphokines
(metabolism)
- Mice
- Mice, Inbred C57BL
- Piperazines
(pharmacology)
- Platelet-Derived Growth Factor
(metabolism)
- Pyrimidines
(pharmacology)
- Receptor, Platelet-Derived Growth Factor alpha
(antagonists & inhibitors)
- Stroke
(drug therapy)
- Tissue Plasminogen Activator
(metabolism)
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