© 1999 American Heart Association, Inc.
Thrombosis |
Tissue Plasminogen Activator (tPA) Deficiency Exacerbates Cerebrovascular Fibrin Deposition and Brain Injury in a Murine Stroke Model
Studies in tPA-Deficient Mice and Wild-Type Mice on a Matched Genetic Background
From the Department of Neurosurgery (P.T., L.W., S.Y., M.H.W., B.V.Z.), University of Southern California, Los Angeles; the Neuroscience Center (N.S.), University of Colorado Health Sciences Center, Denver; the Division of Neurosurgery (J.G.M., B.V.Z.), Children’s Hospital Los Angeles, University of Southern California, Los Angeles; Scripps Research Institute (J.H.G.), La Jolla, Calif; and the Center for Transgene Technology and Gene Therapy (P.C.), Flanders, Leuven, Belgium.
Correspondence to Berislav V. Zlokovic, MD, PhD, 2025 Zonal Ave, RMR 506, Los Angeles, CA 90033. E-mail zlokovic{at}hsc.usc.edu
Abstract—Although the serine protease, tissue plasminogen activator (tPA), is approved by the US Food and Drug Administration for therapy to combat focal cerebral infarction, the basic concept of thrombolytic tPA therapy for stroke was challenged by recent studies that used genetically manipulated tPA-deficient (tPA-/-) mice, which suggested that tPA mediates ischemic neuronal damage. However, those studies were potentially flawed because the genotypes of tPA-/- and wild-type control mice were not entirely clear, and ischemic neuronal injury was evaluated in isolation of tPA effects on brain thrombosis. Using mice with appropriate genetic backgrounds and a middle cerebral artery occlusion stroke model with nonsiliconized thread, which does lead to microvascular thrombus formation, in the present study we determined the risk for cerebrovascular thrombosis and neuronal injury in tPA-/- and genetically matched tPA+/+ mice subjected to transient focal ischemia. Cerebrovascular fibrin deposition and the infarction volume were increased by 8.2- and 6.7-fold in tPA-/- versus tPA+/+ mice, respectively, and these variables were correlated with reduced cerebral blood flow up to 58% (P<0.05) and impaired motor neurological score by 70% (P<0.05). Our findings indicate that tPA deficiency exacerbates ischemia-induced cerebrovascular thrombosis and that endogenous tPA protects the brain from an ischemic insult, presumably through its thrombolytic action. In addition, our study emphasizes the importance of appropriate genetic controls in murine stroke research.
Key Words: tissue plasminogen activator • cerebrovascular events • fibrin • neuroprotection • ischemia
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