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Annexin A2 Plus Low-Dose Tissue Plasminogen Activator Combination Attenuates Cerebrovascular Dysfunction After Focal Embolic Stroke of Rats

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Abstract

Previous studies showed recombinant annexin A2 (rA2) in combination with low-dose tissue-type plasminogen activator (tPA) improved thrombolytic efficacy and long-term neurological outcomes after embolic focal ischemia in rats. The objective of this study was to investigate the effects and mechanisms of the combination in early BBB integrity and cerebrovascular patency in the rat focal embolic stroke model. Ischemic brain infarct volume and hemorrhagic transformation were quantified at 24 h after stroke. At an earlier time point, 16 h after stroke, BBB integrity was evaluated by IgG extravasation, and the involved mechanisms were assessed for tight junction ZO-1 and adhesion junction ve-cadherin protein expression, matrix metalloproteinase activation, extracellular matrix collagen IV and endothelial barrier antigen expression, and activation of microglia/macrophages and astrocytes. While at the same time point, cerebrovascular patency was assessed by intravascular fibrin and platelet depositions. At 24 h after stroke, the combination showed significant reduction in brain infarction and intracerebral hemorrhage. At 16 h after stroke onset, the combination therapy significantly reduced BBB disruption, and improved preservation of the junction proteins ZO-1 and ve-cadherin, decreased activation of matrix metalloproteinase, inhibited degradation of extracellular matrix collagen IV and endothelial barrier antigen, and reduced microglia/macrophage and astrocytes activations. Meanwhile, the combination also significantly improved cerebrovascular patency by reducing intravascular fibrin and platelet depositions in the peri-infarct brain tissues. These results suggest the beneficial effects of the rA2 plus low-dose tPA combination may be mediated in part by the amelioration of BBB disruption and improvement of cerebrovascular patency.

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Authors and Affiliations

  1. Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China

    Xiang Fan & Xiumei Gao

  2. Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, MA, USA

    Xiang Fan, Yinghua Jiang, Zhanyang Yu, Qi Liu, Shuzhen Guo, Klaus van Leyen, MingMing Ning, Eng H. Lo & Xiaoying Wang

  3. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Yinghua Jiang & Xiaochuan Sun

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  1. Xiang Fan
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Correspondence to Xiang Fan or Xiaoying Wang.

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This work was in part supported by the National Institute of Health grants R01-NS065998 and UO1-NS072324 (to X.W.) and National Natural Science Foundation of China (No. 81622051) (to X.F.).

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All national and institutional guidelines for the care and use of animals were followed.

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Fan, X., Jiang, Y., Yu, Z. et al. Annexin A2 Plus Low-Dose Tissue Plasminogen Activator Combination Attenuates Cerebrovascular Dysfunction After Focal Embolic Stroke of Rats. Transl. Stroke Res. 8, 549–559 (2017). https://doi.org/10.1007/s12975-017-0542-6

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