tPA Modulation of the Blood–Brain Barrier: A Unifying Explanation for the Pleiotropic Effects of tPA in the CNS

Linda Fredriksson; Daniel A. Lawrence; Robert L. Medcalf

doi:10.1055/s-0036-1586229

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2017; 43(2): 154-168
DOI: 10.1055/s-0036-1586229

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

tPA Modulation of the Blood–Brain Barrier: A Unifying Explanation for the Pleiotropic Effects of tPA in the CNS

Linda Fredriksson

¹Division of Vascular Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden

²Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan

,

Daniel A. Lawrence

²Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan

³Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan

,

Robert L. Medcalf

⁴Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Monash University, Melbourne, Australia

› Author Affiliations

Abstract

The plasminogen activation (PA) system is best known for its role in fibrinolysis. However, it has also been shown to regulate many nonfibrinolytic functions in the central nervous system (CNS). In particular, tissue-type plasminogen activator (tPA) is reported to have pleiotropic activities in the CNS, regulating events such as neuronal plasticity, excitotoxicity, and cerebrovascular barrier integrity, whereas urokinase-type plasminogen activator is mainly associated with tissue remodeling and cell migration. It has been suggested that the role tPA plays in controlling barrier integrity may provide a unifying mechanism for the reported diverse, and often opposing, functions ascribed to tPA in the CNS. Here we will review the possibility that the pleiotropic effects reported for tPA in physiologic and pathologic processes in the CNS may be a consequence of its role in the neurovascular unit in regulation of cerebrovascular responses and subsequently parenchymal homeostasis. We propose that this might offer an explanation for the ongoing debate regarding the neurotoxic versus neuroprotective roles of tPA.

Keywords

tPA - PDGF-CC - PDGFR-α - PAI-1 - neuroserpin - blood–brain barrier

Full Text

References

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