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Published on: September 12, 2018
Hypoxic Human Microglia Promote Angiogenesis Through Extracellular Vesicle Release
Alessandra Maria Testa1,2, Livia Vignozzi1, Diana Corallo3
1Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy.
Abstract:
Microglia, the brain-resident immune cells, orchestrate neuroinflammatory responses and are crucial in the progression of neurological diseases, including ischemic stroke (IS), which accounts for approximately 85% of all strokes worldwide. Initially deemed detrimental, microglial activation has been shown to perform protective functions in the ischemic brain. Besides their effects on neurons, microglia play a role in promoting post-ischemic angiogenesis, a pivotal step for restoring oxygen and nutrient supply. However, the molecular mechanisms underlying microglia-endothelial cell interactions remain largely unresolved, particularly in humans. Using both in vitro and in vivo models, we investigated the angiogenic signature and properties of extracellular vesicles (EVs) released by human microglia upon hypoxia-reperfusion stimulation. EVs were isolated and characterized in terms of their size, concentration, and protein content. Their angiogenic potential was evaluated using endothelial cell assays and a zebrafish xenograft model. The in vivo effects were further assessed in a mouse model of ischemic stroke. Our findings identified key proteins orchestrating the pro-angiogenic functions of human microglial EVs under hypoxic conditions. In vitro assays demonstrated that hypoxic EVs (hypEVs) promoted endothelial cell migration and tube formation. In vivo, hypEVs induced vessel sprouting in zebrafish and increased microvessel density in the perilesional area of mice following ischemic stroke.
Insights
Human microglia release extracellular vesicles (EVs) that promote blood vessel growth after stroke. These microglial EVs, particularly under hypoxic conditions, show significant potential in enhancing recovery by supporting angiogenesis.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are key immune cells in the brain, influencing neuroinflammation and neurological disease progression, including ischemic stroke (IS).
- While initially considered harmful, activated microglia exhibit protective roles in the ischemic brain, notably promoting post-ischemic angiogenesis.
- The precise molecular mechanisms of microglia-endothelial cell interactions in promoting angiogenesis remain poorly understood, especially in human systems.
Purpose of the Study:
- To investigate the angiogenic signature and properties of extracellular vesicles (EVs) secreted by human microglia under hypoxia-reperfusion.
- To elucidate the molecular mechanisms by which microglial EVs influence endothelial cells and angiogenesis.
- To assess the therapeutic potential of these microglial EVs in models of ischemic stroke.
Main Methods:
- Isolation and characterization of extracellular vesicles (EVs) from human microglia subjected to hypoxia-reperfusion.
- In vitro assessment of EV angiogenic potential using endothelial cell migration and tube formation assays.
- In vivo evaluation of EV efficacy in zebrafish xenograft and mouse ischemic stroke models.
Main Results:
- Extracellular vesicles (EVs) from hypoxic human microglia (hypEVs) were isolated and characterized.
- In vitro studies showed that hypEVs significantly enhanced endothelial cell migration and tube formation.
- In vivo studies demonstrated that hypEVs promoted vessel sprouting in zebrafish and increased microvessel density in the perilesional area of stroke-affected mice.
Conclusions:
- Human microglial extracellular vesicles (EVs) possess potent pro-angiogenic properties, particularly under hypoxic conditions.
- These findings identify key proteins involved in microglial EV-mediated angiogenesis, offering potential therapeutic targets.
- Microglial EVs represent a promising cell-free therapeutic strategy for promoting recovery after ischemic stroke.
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