Maintaining Cerebrovascular Integrity

Abstract

The serine protease tissue plasminogen activator (tPA, a clot-busting enzyme that can be used to treat acute ischemic stroke) must be administered within hours of the onset of stroke symptoms, markedly limiting its clinical utility. With a delay of more than three hours, the risk of catastrophic brain hemorrhage as a complication of intravenous tPA treatment outweighs the potential benefits (see Rieckmann). Su et al ., a group of researchers who previously showed that tPA increases cerebrovascular permeability independently of plasminogen (a substrate critical to tPA’s thrombolytic effects) and that platelet-derived growth factor-CC (PDGF-CC) is a tPA target, investigated the role of PDGF-CC in regulating cerebrovascular permeability. Intraventricular administration of tPA increased cerebrovascular permeability in mice, as did active PDGF-CC; moreover, the tPA-mediated increase was inhibited by neutralizing antibodies directed against PDGF-CC. tPA and PDGF-CC produced similar morphological changes in cerebral vasculature, predominantly areas of apparent fluid accumulation around arterioles; indeed, tpA, PDGF-CC, and the PDGF receptor-α (PDGFR-α) were all associated with brain arterioles, with PDGFR-α expressed in perivascular astrocytes. Middle cerebral artery occlusion (MCAO, a model of ischemic stroke) led to an increase in PDGFR-α phosphorylation (indicative of activation) in wild-type mice but not in mice lacking endogenous tPA. MCAO elicited an increase in cerebrovascular permeability, and treatment with the PDGFR-α inhibitor imatinib 1 hour after MCAO reduced this response. Imatinib also decreased the volume of infarct seen 72 hours after MCAO and decreased cerebral hemorrhage associated with tPA treatment administered 5 hours after MCAO. Thus, the authors propose that endogenous PDGF-CC may regulate blood-brain barrier permeability after ischemic stroke and that targeting signaling mediated through PDGF-CC and PDGFR-α with agents such as imatinib (an anticancer drug also known as Gleevec) may extend the therapeutic window for tPA treatment. E. J. Su, L. Fredriksson, M. Geyer, E. Folestad, J. Cale, J. Andrae, Y. Gao, K. Pietras, K. Mann, M. Yepes, D. K. Strickland, C. Betsholtz, U. Eriksson, D. A. Lawrence, Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat. Med . 14 , 731-737 (2008). [PubMed] P. Rieckmann, Imatinib buys time for brain after stroke. Nat. Med . 14 , 712-713 (2008). [PubMed]