Differential Effects of Paracrine Factors on the Survival of Cells of the Neurovascular Unit during Oxygen Glucose Deprivation

Abstract

Background

Disruption of the neurovascular unit following cerebral ischemia affects protetive function of the blood-brain barrier, thus contributing to vasogenic edema and hemorrhagic transformation.

Aims

This study explored the effects of mediators released from neurovascular unit cells on death of brain endothelial cells, astrocytes, pericytes, and microglia during oxygen glucose deprivation.

Methods

Rat primary cell cultures were exposed either to oxygen glucose deprivation or control conditions. Cell death and released angiogenic factors were assessed from media collected from cultures. For some experiments, astrocyte-conditioned media, pericyte-conditioned media, and microglia-conditioned media, collected from the corresponding cell culture after six-hour oxygen glucose deprivation, were added to the media during oxygen glucose deprivation incubations.

Results

Brain endothelial cells were more susceptible to death following oxygen glucose deprivation than other neurovascular unit cells. Neither astrocyte-conditioned media nor vascular endothelial growth factor165 were protective for pericytes or brain endothelial cells during oxygen glucose deprivation. Vascular endothelial growth factor receptor antagonist significantly reduced cell death of brain endothelial cells treated with astrocyte-conditioned media or vascular endothelial growth factor165. Pericyte-conditioned media were protective for brain endothelial cells and microglia, but this was not mediated by pericyte-released angiopoietin 1. Soluble angiopoietin 1/angiopoietin 2 receptor Tie2 was protective for brain endothelial cells. Microglia-conditioned media were protective for astrocytes and brain endothelial cells, possibly through transforming growth factor β1 or interleukin 6.

Conclusion

Microglia-derived signaling molecules, but not angiogenic factors, were protective for neurovascular unit cells during oxygen glucose deprivation. This finding could identify a potential therapeutic target for ischemic stroke.

Keywords

brain endothelial cells neurovascular unit oxygen glucose deprivation angiopoietin transforming growth factor β1 vascular endothelial growth factor

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