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Targeting platelet GPVI plus rt-PA administration but not α2β1-mediated collagen binding protects against ischemic brain damage in mice

Please always quote using this URN: urn:nbn:de:bvb:20-opus-201700
  • 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 toPlatelet 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.show moreshow less

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Metadaten
Author: Michael K. Schuhmann, Peter Kraft, Michael Bieber, Alexander M. Kollikowski, Harald Schulze, Bernhard Nieswandt, Mirko Pham, David Stegner, Guido Stoll
URN:urn:nbn:de:bvb:20-opus-201700
Document Type:Journal article
Faculties:Medizinische Fakultät / Neurologische Klinik und Poliklinik
Medizinische Fakultät / Institut für Experimentelle Biomedizin
Medizinische Fakultät / Abteilung für Neuroradiologie
Language:English
Parent Title (English):International Journal of Molecular Science
Year of Completion:2019
Volume:20
Issue:8
Pagenumber:2019
Source:International Journal of Molecular Science 2019, 20(8), 2019; https://doi.org/10.3390/ijms20082019
DOI:https://doi.org/10.3390/ijms20082019
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:glycoprotein VI; integrin α2; intracranial bleeding; ischemic stroke; recombinant tissue-type plasminogen activator; transient middle cerebral artery occlusion
Release Date:2020/03/23
Collections:Open-Access-Publikationsfonds / Förderzeitraum 2019
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International