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Targeting Platelet GPVI Plus rt-PA Administration but Not α2β1-Mediated Collagen Binding Protects against Ischemic Brain Damage in Mice

1
Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany
2
Department of Neurology, Klinikum Main-Spessart, 97816 Lohr, Germany
3
Department of Neuroradiology, University Hospital Würzburg, 97080 Würzburg, Germany
4
Institute of Experimental Biomedicine-Department I, University Hospital Würzburg, 97080 Würzburg, Germany
5
Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(8), 2019; https://doi.org/10.3390/ijms20082019
Received: 6 March 2019 / Revised: 9 April 2019 / Accepted: 22 April 2019 / Published: 24 April 2019
Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2−/− mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke. View Full-Text
Keywords: ischemic stroke; integrin α2; glycoprotein VI; recombinant tissue-type plasminogen activator; intracranial bleeding; transient middle cerebral artery occlusion ischemic stroke; integrin α2; glycoprotein VI; recombinant tissue-type plasminogen activator; intracranial bleeding; transient middle cerebral artery occlusion
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MDPI and ACS Style

Schuhmann, M.K.; Kraft, P.; Bieber, M.; Kollikowski, A.M.; Schulze, H.; Nieswandt, B.; Pham, M.; Stegner, D.; Stoll, G. Targeting Platelet GPVI Plus rt-PA Administration but Not α2β1-Mediated Collagen Binding Protects against Ischemic Brain Damage in Mice. Int. J. Mol. Sci. 2019, 20, 2019. https://doi.org/10.3390/ijms20082019

AMA Style

Schuhmann MK, Kraft P, Bieber M, Kollikowski AM, Schulze H, Nieswandt B, Pham M, Stegner D, Stoll G. Targeting Platelet GPVI Plus rt-PA Administration but Not α2β1-Mediated Collagen Binding Protects against Ischemic Brain Damage in Mice. International Journal of Molecular Sciences. 2019; 20(8):2019. https://doi.org/10.3390/ijms20082019

Chicago/Turabian Style

Schuhmann, Michael K., Peter Kraft, Michael Bieber, Alexander M. Kollikowski, Harald Schulze, Bernhard Nieswandt, Mirko Pham, David Stegner, and Guido Stoll. 2019. "Targeting Platelet GPVI Plus rt-PA Administration but Not α2β1-Mediated Collagen Binding Protects against Ischemic Brain Damage in Mice" International Journal of Molecular Sciences 20, no. 8: 2019. https://doi.org/10.3390/ijms20082019

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