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

Anna R Malik; Janet Lips; Malgorzata Gorniak-Walas; Diede W M Broekaart; Antonino Asaro; Melanie T C Kuffner; Christian J Hoffmann; Majed Kikhia; Monika Dopatka; Philipp Boehm-Sturm; Susanne Mueller; Ulrich Dirnagl; Eleonora Aronica; Christoph Harms; Thomas E Willnow

doi:10.1002/glia.23778

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

Anna R Malik^*, Janet Lips, Malgorzata Gorniak-Walas, Diede W M Broekaart, Antonino Asaro, Melanie T C Kuffner, Christian J Hoffmann, Majed Kikhia, Monika Dopatka, Philipp Boehm-Sturm, Susanne Mueller, Ulrich Dirnagl, Eleonora Aronica, Christoph Harms, Thomas E Willnow^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Glia
Vol/bind	68
Nummer	6
Sider (fra-til)	1304-1316
Antal sider	13
ISSN	0894-1491
DOI	https://doi.org/10.1002/glia.23778
Status	Udgivet - jun. 2020
Udgivet eksternt	Ja

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10.1002/glia.23778

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Malik, A. R., Lips, J., Gorniak-Walas, M., Broekaart, D. W. M., Asaro, A., Kuffner, M. T. C., Hoffmann, C. J., Kikhia, M., Dopatka, M., Boehm-Sturm, P., Mueller, S., Dirnagl, U., Aronica, E., Harms, C., & Willnow, T. E. (2020). SorCS2 facilitates release of endostatin from astrocytes and controls post-stroke angiogenesis. Glia, 68(6), 1304-1316. https://doi.org/10.1002/glia.23778

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title = "SorCS2 facilitates release of endostatin from astrocytes and controls post-stroke angiogenesis",

abstract = "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.",

keywords = "VPS10P domain receptors, cytokine, glial scar, ischemia, protein sorting",

author = "Malik, {Anna R} and Janet Lips and Malgorzata Gorniak-Walas and Broekaart, {Diede W M} and Antonino Asaro and Kuffner, {Melanie T C} and Hoffmann, {Christian J} and Majed Kikhia and Monika Dopatka and Philipp Boehm-Sturm and Susanne Mueller and Ulrich Dirnagl and Eleonora Aronica and Christoph Harms and Willnow, {Thomas E}",

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doi = "10.1002/glia.23778",

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T1 - SorCS2 facilitates release of endostatin from astrocytes and controls post-stroke angiogenesis

AU - Malik, Anna R

AU - Lips, Janet

AU - Gorniak-Walas, Malgorzata

AU - Broekaart, Diede W M

AU - Asaro, Antonino

AU - Kuffner, Melanie T C

AU - Hoffmann, Christian J

AU - Kikhia, Majed

AU - Dopatka, Monika

AU - Boehm-Sturm, Philipp

AU - Mueller, Susanne

AU - Dirnagl, Ulrich

AU - Aronica, Eleonora

AU - Harms, Christoph

AU - Willnow, Thomas E

PY - 2020/6

Y1 - 2020/6

N2 - 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.

AB - 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.

KW - VPS10P domain receptors

KW - cytokine

KW - glial scar

KW - ischemia

KW - protein sorting

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U2 - 10.1002/glia.23778

DO - 10.1002/glia.23778

M3 - Journal article

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SN - 0894-1491

VL - 68

SP - 1304

EP - 1316

JO - Glia

JF - Glia

IS - 6

ER -

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

Abstract

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