Activation of Sigma-1 Receptor Enhanced Pericyte Survival via the Interplay Between Apoptosis and Autophagy: Implications for Blood–Brain Barrier Integrity in Stroke

Abstract

Stroke is a cerebrovascular disorder that affects many people worldwide. Pericytes play an important role in stroke progression and recovery. The sigma-1 receptor (σ-1R) signaling pathway has been suggested as having promising neuroprotective potential in treating stroke; however, whether σ-1R activation regulates pericyte function remains unknown. The aim of this study was to elucidate the role of σ-1R and a novel σ-1R agonist in pericytes following ischemic stroke. An ischemic stroke animal model was induced by photothrombotic middle cerebral artery occlusion (pMCAO) in σ-1R knockout (KO) and wild-type (WT) mice. After pMCAO, there was significant pericyte loss and coverage in σ-1R KO mice compared with WT mice as determined using transmission electron microscopy, immunofluorescence staining, and western blot. Interestingly, a novel σ-1R agonist decreased infarct volume and blood–brain barrier damage with a concomitant amelioration of pericyte loss, as determined by western blot. Further studies indicated that cell apoptosis and autophagy were induced in an in vivo pMCAO ischemic stroke animal model and an in vitro oxygen glucose deprivation-treatment group. Inhibition of autophagy using a pharmacological approach significantly mitigated pericyte apoptosis, suggesting that autophagy was upstream of apoptosis in pericytes. Both in vivo and in vitro studies indicated that the σ-1R agonist significantly decreased cell apoptosis via inhibition of autophagy with a subsequent enhancement of pericyte survival. This study identified the unique roles for σ-1R in mediating pericyte survival via the regulation of the interplay between apoptosis and autophagy, suggesting that a novel σ-1R agonist may be a promising therapeutic agent for the treatment of stroke patients.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81761138048, 81673410, and 81603090), Jiangsu Innovation & Entrepreneurship Talent Program, Jiangsu Innovation & Entrepreneurship Team Program, National Key Research and Development Program of China (2017YFA0104303), and the Fundamental Research Funds for the Central Universities (Nos. 2242018K41007, 2242018K41059, 2242019K40133, and 2242019K40125).

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Zhang, Y., Zhang, X., Wei, Q. et al. Activation of Sigma-1 Receptor Enhanced Pericyte Survival via the Interplay Between Apoptosis and Autophagy: Implications for Blood–Brain Barrier Integrity in Stroke. Transl. Stroke Res. 11, 267–287 (2020). https://doi.org/10.1007/s12975-019-00711-0

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Keywords

  • Stroke
  • Sigma-1 receptor
  • Blood–brain barrier
  • Pericyte
  • Apoptosis
  • Autophagy