期刊
NATURE MEDICINE
卷 14, 期 7, 页码 731-737出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1787
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资金
- NHLBI NIH HHS [HL50784, P01 HL054710-12, HL54710, R01 HL050784-09, P01 HL057346, P01 HL054710-11A10006, R01 HL055374-12, HL55374, R01 HL055374-09, HL55747, P01 HL054710-120006, R01 HL055747, R01 HL055374-10, R01 HL055747-11, R01 HL055374-11A1, R01 HL055747-10, P01 HL054710-11A1, R01 HL050784, R01 HL055374, HL57346, P01 HL057346-11A18577, P01 HL054710] Funding Source: Medline
- NINDS NIH HHS [R01 NS049478-04, R01 NS049478, R01 NS079331, NS49478, R01 NS062073, R01 NS091201] Funding Source: Medline
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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