Platelet glycoprotein Ibα is an important mediator of ischemic stroke in mice

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Abstract

Background

Platelets play an important role in ischemic stroke. GPIbα is a major platelet receptor that is critical for platelet adhesion to exposed subendothelial matrix components at sites of vascular damage.

Methods

In this study, we used transgenic mice in which the extracellular part of GPIbα is replaced by human interleukin 4-receptor (GPIbα/IL4Rα). We observed normal brain vasculature in these mice. We compared infarct size in GPIbα/IL4Rα and wild-type (WT) mice 23 hours after 1-hour transient middle cerebral artery occlusion (tMCAO). In addition, the functional outcome was evaluated using a modified Bederson score.

Results

We found a significantly smaller infarct size in GPIbα/IL4Rα mice compared to WT mice (38.0 ± 6.5 mm ³vs. 74.2 ± 8.6 mm ³, p < 0.001). The decrease in infarct size was functionally relevant as indicated by a significantly better functional Bederson score in GPIbα/IL4Rα mice compared to WT animals (1.3 ± 0.4 vs. 2.7 ± 0.3, p < 0.05).

Conclusions

Our data illustrate and further confirm the important role of platelet GPIbα in ischemic stroke, suggesting that targeted inhibition of this receptor may open new avenues in stroke treatment.

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Most cited references 21

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Monofilament intraluminal middle cerebral artery occlusion in the mouse.

Nikola Lessov, Howard Clark, F Eckenstein … (1997)

The rat middle cerebral artery (MCA) occlusion model with an intraluminal filament is well characterized with a two hour period of occlusion in widespread use. The recent availability of transgenic animals has led to an interest in adapting the MCA model in the mouse. To date the model has not been well characterized in the mouse. We performed the present study to compare different durations of MCA occlusion and to validate new functional assessments in this model. The MCA occlusion model (5-0 filament) was used. Swiss-Webster mice, 24-44 g, were randomly assigned to four groups: one hour of occlusion; two hours of occlusion; three hours of occlusion; or permanent occlusion. At 48 hours post-ischemia, the animals were rated on three neurologic function scales, and then the brains were removed for lesion size determination. Overall, there was a significant difference in lesion volume (p < 0.001) between the groups. In the permanent group of mice, the average lesion volume was 78.41 +/- 17.47 mm (n = 12); two and three hours of ischemia produced 51.29 +/- 29.82 mm3 (n = 11) and 54.85 mm3 (n = 13), respectively, significantly different than the one hour group 14.84 +/- 31.34 mm3 (n = 11). All three functional scoring systems found significant overall differences between the four groups with our detailed General and Focal scores producing more robust between group treatment differences and showing correlation coefficients of r = 0.766 and r = 0.788, respectively to infarct volume. The MCA filament occlusion model can be successfully adapted in the mouse with either two or three hour occlusions producing reliable infarcts. New functional scoring systems unique to the mouse appear to add additional information.

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von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke.

Qiao Zhao, Joon Yang, Friedrich Scheiflinger … (2009)

Stroke is a leading cause of death and disability. The only therapy available is recombinant tissue plasminogen activator, but side effects limit its use. Platelets play a crucial role during stroke, and the inflammatory reaction promotes neurodegeneration. von Willebrand factor (VWF), an adhesion molecule for platelets, is elevated in patients with acute stroke. The activity of VWF is modulated by ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) that cleaves VWF to smaller less-active forms. We recently documented that ADAMTS13 negatively regulates both thrombosis and inflammation. We report that deficiency or reduction of VWF reduces infarct volume up to 2-fold after focal cerebral ischemia in mice, thus showing the importance of VWF in stroke injury. In contrast, ADAMTS13 deficiency results in larger infarctions, but only in mice that have VWF. Importantly, infusion of a high dose of recombinant human ADAMTS13 into a wild-type mouse immediately before reperfusion reduces infarct volume and improves functional outcome without producing cerebral hemorrhage. Furthermore, recombinant ADAMTS13 did not enhance bleeding in a hemorrhagic stroke model. Our findings show the importance of VWF in regulating infarction and suggest that recombinant ADAMTS13 could be considered as a new therapeutic agent for prevention and/or treatment of stroke.

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High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability.

Tamara N Bongers, Moniek P M de Maat, Mary-Lou P J van Goor … (2006)

Elevated von Willebrand factor (vWF) concentrations are associated with an increased risk of ischemic heart disease. Several factors influence vWF antigen levels and activity, including blood group, genetic variability, acute-phase response, and proteolysis by A Disintegrin and Metalloprotease with ThromboSpondin motif (ADAMTS13), a determinant of proteolytic cleavage of vWF. We assessed how these factors affect the relation between vWF and the occurrence of stroke to understand the underlying mechanism. In a case-control study of 124 first-ever ischemic stroke patients and 125 age- and sex-matched controls, we studied vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), ADAMTS13 activity, the -1793C/G polymorphism in the vWF gene, and C-reactive protein. vWF antigen and activity levels were significantly higher in cases than in controls. The relative risk of ischemic stroke was highest in individuals in the upper quartile of vWF:Ag (odds ratio, 3.2; 95% CI, 1.4 to 7.5) and vWF:RCo (odds ratio, 2.1; 95% CI, 0.9 to 4.8) compared with individuals in the lowest quartiles. In individuals with ADAMTS13 in the lowest quartile, the relative risk of stroke was 1.7 (95% CI, 0.7 to 3.9) compared with the highest quartile. C-reactive protein, ADAMTS13, and genetic variation did not affect the association between vWF and the relative risk of stroke, whereas blood group did affect the association. vWF antigen and activity are associated with the occurrence of acute ischemic stroke. This relation is unaffected by the severity of the acute-phase response or by genetic variation or degradation.

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Author and article information

Journal

Journal ID (nlm-ta): Exp Transl Stroke Med

Title: Experimental & Translational Stroke Medicine

Publisher: BioMed Central

ISSN (Electronic): 2040-7378

Publication date Collection: 2011

Publication date (Electronic): 13 September 2011

Volume: 3

Page: 9

Affiliations

[1 ]Immune Disease Institute, (3 Blackfan Circle), Boston, (MA 02115), USA

[2 ]Program in Cellular and Molecular Medicine, Children's Hospital Boston, (300 Longwood Avenue), Boston, (MA 02115), USA

[3 ]Department of Pediatrics, Harvard Medical School, (25 Shattuck Street), Boston, (MA 02115), USA

[4 ]Laboratory for Thrombosis Research, KULeuven Campus Kortrijk, (E. Sabbelaan 53), Kortrijk, (B-8500), Belgium

[5 ]Department of Neurology, University of Wuerzburg, (Josef-Schneider-Str. 11), Wuerzburg, (D-97080), Germany

Article

Publisher ID: 2040-7378-3-9

DOI: 10.1186/2040-7378-3-9

PMC ID: 3180255

PubMed ID: 21914206

SO-VID: fc7320a1-7f23-4223-8190-a95d62c97591

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 1 July 2011

Date accepted : 13 September 2011

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Platelet glycoprotein Ibα is an important mediator of ischemic stroke in mice

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Abstract

Background

Methods

Results

Conclusions

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Karger: Cardiovascular System

Most cited references 21

Monofilament intraluminal middle cerebral artery occlusion in the mouse.

von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke.

High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability.

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