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SorCS2 facilitates release of endostatin from astrocytes and controls post-stroke angiogenesis

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DOI

  • Anna R Malik, Max Delbrueck Center for Molecular Medicine, Polish Academy of Sciences
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  • Janet Lips, Charité – Universitätsmedizin Berlin, Berlin Institute of Health
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  • Malgorzata Gorniak-Walas
  • Diede W M Broekaart, University of Amsterdam
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  • Antonino Asaro, Max Delbrueck Center for Molecular Medicine
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  • Melanie T C Kuffner, Charité – Universitätsmedizin Berlin, Berlin Institute of Health
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  • Christian J Hoffmann, Charité – Universitätsmedizin Berlin, Berlin Institute of Health
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  • Majed Kikhia, Charité – Universitätsmedizin Berlin, Berlin Institute of Health
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  • Monika Dopatka, Charité – Universitätsmedizin Berlin, Berlin Institute of Health
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  • Philipp Boehm-Sturm, Charité – Universitätsmedizin Berlin, Berlin Institute of Health
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  • Susanne Mueller, Charité – Universitätsmedizin Berlin, Berlin Institute of Health
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  • Ulrich Dirnagl, Charité – Universitätsmedizin Berlin, Berlin Institute of Health, German Centre for Neurodegenerative Diseases
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  • Eleonora Aronica, University of Amsterdam, Stichting Epilepsie Instellingen Nederland (SEIN)
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  • Christoph Harms, Charité – Universitätsmedizin Berlin, Berlin Institute of Health
  • ,
  • Thomas E Willnow

SorCS2 is an intracellular sorting receptor of the VPS10P domain receptor gene family recently implicated in oxidative stress response. Here, we interrogated the relevance of stress-related activities of SorCS2 in the brain by exploring its role in ischemic stroke in mouse models and in patients. Although primarily seen in neurons in the healthy brain, expression of SorCS2 was massively induced in astrocytes surrounding the ischemic core in mice following stroke. Post-stroke induction was likely a result of increased levels of transforming growth factor β1 in damaged brain tissue, inducing Sorcs2 gene transcription in astrocytes but not neurons. Induced astrocytic expression of SorCS2 was also seen in stroke patients, substantiating the clinical relevance of this observation. In astrocytes in vitro and in the mouse brain in vivo, SorCS2 specifically controlled release of endostatin, a factor linked to post-stroke angiogenesis. The ability of astrocytes to release endostatin acutely after stroke was lost in mice deficient for SorCS2, resulting in a blunted endostatin response which coincided with impaired vascularization of the ischemic brain. Our findings identified activated astrocytes as a source for endostatin in modulation of post-stroke angiogenesis, and the importance of the sorting receptor SorCS2 in this brain stress response.

Original languageEnglish
JournalGlia
Volume68
Issue6
Pages (from-to)1304-1316
Number of pages13
ISSN0894-1491
DOIs
Publication statusPublished - Jun 2020
Externally publishedYes

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© 2020 The Authors. Glia published by Wiley Periodicals, Inc.

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