The role of glycoprotein Ibalpha and von Willebrand factor interaction in stroke development

Summary

Ischaemic stroke is a devastating disease with limited treatment options due to numerous uncertainties regarding the underlying pathophysiology. The contribution of glycoprotein (GP)Ibα and von Willebrand factor (VWF) in stroke development has only recently been established in mice. Complete blockade of GPIbα led to a significant reduction of infarct volumes in mice undergoing one hour of transient middle cerebral artery occlusion (tMCAO). High shear-induced changes in VWF confirmation are a prerequisite for VWF binding to collagen and GPIbα expressed on platelets. Importantly, transgenic VWF^−/−mice were similarly protected against ischemic stroke after tMCAO, and hydrodynamic injection of a VWF-encoding plasmid restored VWF serum levels and the susceptibility towards stroke. Secreted VWF is rapidly cleaved by ADAMTS13. Accordingly, ADAMTS13 deficient mice developed larger infarction after tMCAO, while infusion of recombinant ADAMTS13 into wild-type mice was strokeprotective. In conclusion, there is compelling evidence that GPIbα/VWF interactions and downstream signaling via phospholipase D1 (PLD1) provide new therapeutic targets in ischemic stroke.

Zusammenfassung

Der ischämische Schlaganfall ist eine häufige Erkrankung mit begrenzten Therapieoptionen, dessen Pathophysiologie noch weitgehend unverstanden ist. Neueste Untersuchungen belegen die besondere Bedeutung von Glykoprotein(GP) Ibα und von-Willebrand-Faktor (VWF) in der Entstehung von ischämischen Hirnläsionen. Die Blockade von GPIbα führte bei Mäusen zu einer Reduktion des Infarktvolumens nach transientem Verschluss der Arteria cerebri media (tMCAOModell). VWF unterliegt unter hohen arteriellen Flussgeschwindigkeiten einer Konformationsänderung, die Voraussetzung für die Bindung an Kollagen und an GPIbα auf Thrombozyten ist. VWF-defiziente Mäuse waren ebenfalls vor Schlaganfällen geschützt, nach Gentransfer von VWF mit partieller Rekonstitution des Plasmaspiegels ging dieser Schutz wieder verloren. Freigesetzter VWF wird im Blut durch das Enzym ADAMTS 13 gespalten, um eine unkontrollierte Thrombenbildung zu verhindern. Entsprechend entwickelten sich bei ADAMTS13-defizienten Mäusen größere Infarkte. GPIbα/VWF-Interaktionen und nachgeschaltete Signalkaskaden über Phospholipase D1 (PLD1) stellen viel versprechende Targets zur Prävention und Behandlung des ischämischen Schlaganfalls dar.

Keywords

Von Willebrand factor - thrombus formation - cerebral ischaemia

Schlüsselwörter

Von-Willebrand-Faktor - Thrombusbildung - Schlaganfall

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