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Exosomal Src from hypoxic vascular smooth muscle cells exacerbates ischemic brain injury by promoting M1 microglial

Xiaoting Zhang1, Jingpei Guo1, Junbin Liu1

  • 1Center of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Center of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China.

Neurochemistry International
|July 31, 2024
PubMed

Insights

Hypoxic vascular smooth muscle cell exosomes promote M1 microglia activation, worsening ischemic stroke (IS) brain injury. Inhibiting Src in these exosomes offers a potential therapeutic strategy for IS by reducing inflammation and protecting neurons.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Inflammatory M1 microglia exacerbate brain injury following ischemic stroke (IS).
  • Vascular smooth muscle cells (VSMCs) under ischemic conditions secrete exosomes.
  • Exosomes regulate microglial polarization, influencing inflammatory responses.

Purpose of the Study:

  • To investigate the role of exosomes derived from hypoxic VSMCs (HExos) in microglial polarization and IS.
  • To identify potential therapeutic targets for mitigating IS-induced brain injury.

Main Methods:

  • Isolation and characterization of exosomes from normoxic (Exos) and hypoxic (HExos) human VSMCs.
  • Co-incubation of HExos with primary human microglia (HM1900) to assess M1 polarization.
  • Proteomic analysis of HExos to identify key mediators (e.g., Src).
  • In vitro and in vivo (pMCAO mouse model) experiments using Src inhibitor dasatinib (DAS).

Main Results:

  • HExos, but not Exos, significantly promoted M1 polarization in HM1900.
  • Src protein was enriched in HExos and upregulated M1 markers in microglia.
  • Dasatinib (DAS) inhibited M1 polarization, promoted M2 phenotype, reduced M1 microglia/macrophages, protected neurons, and improved function in pMCAO mice.

Conclusions:

  • Hypoxic VSMC-derived exosomes promote M1 microglial polarization via Src transmission, contributing to post-IS inflammation.
  • Targeting Src inhibition with agents like dasatinib presents a promising therapeutic strategy for treating ischemic stroke brain injury.
Keywords:
DasatinibIschemic strokeMicroglial polarizationSrcVascular smooth muscle cells-derived exosomes

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