Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke.
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.
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor Michigan 48109-0644, USA.
Enming J
EJ
Su
Linda
L
Fredriksson
Melissa
M
Geyer
Erika
E
Folestad
Jacqueline
J
Cale
Johanna
J
Andrae
Yamei
Y
Gao
Kristian
K
Pietras
Kris
K
Mann
Manuel
M
Yepes
Dudley K
DK
Strickland
Christer
C
Betsholtz
Ulf
U
Eriksson
Daniel A
DA
Lawrence
D000818:Animals; D001549:Benzamides; D001812:Blood-Brain Barrier / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000648:ultrastructure; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D005343:Fibrinolytic Agents / Q000378:metabolism; D000068877:Imatinib Mesylate; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors; D020521:Stroke / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D001549:Benzamides; D005343:Fibrinolytic Agents; D008222:Lymphokines; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; C411423:platelet-derived growth factor C; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D010959:Tissue Plasminogen Activator