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.

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

“…Their pathological importance was underestimated at first. In recent decades, however, astrocytes have been found to not only extensively participate in biological activities in the CNS, including the regulation of the blood-brain barrier, synaptic function and glutamate uptake (Füchtbauer et al, 2011;Haj-Yasein et al, 2011;Murai and Pasquale, 2011;Min and Nevian, 2012;Murphy-Royal et al, 2015), but also play crucial roles in pathological processes, including neurodegenerative diseases, stroke and CNS injuries (Bradford et al, 2009;Kuchibhotla et al, 2009;Wanner et al, 2013;Khakh and Sofroniew, 2015;Malik et al, 2020). After SCI, astrocytes are activated, and some of them rapidly proliferate to form an astrocytic scar border, traditionally referred to as the glial scar.…”

Inflammation-Mediated Angiogenesis in Ischemic Stroke

“…Activated microglia/macrophages have been demonstrated to be the primary sources of TGF-β1 messenger RNA (mRNA) after focal ischemic attack (Lehrmann et al, 1998;Doyle et al, 2010). In addition, astrocytes and neuronal cells may also contribute to the upregulated TGF-β1 expression after IS (Zhu et al, 2001;Malik et al, 2020).…”

Astrocytes in the regulation of cerebrovascular functions

“…Another recently described poststroke astrocytic mechanism contributing to the brain repair is the expression of SorCS2, a member of the VPS10P domain receptor family that is usually expressed solely by neurons. SorCS2 expression was found to be upregulated in astrocytes following ischemia; the protein might control the secretion of endostatin and thus promote angiogenesis (Malik et al, 2020).…”