Astrocytes Regulate Angiogenesis Through the Jagged1-Mediated Notch1 Pathway After Status Epilepticus

Vascular disruptions including blood-brain barrier breakdown and pathologic angiogenesis contribute to the development of epilepsy in normal brains. The Notch signaling pathway is activated in response to seizure activity, and its activation promotes seizures, although its exact role in angiogenesis is poorly understood. Here, we have examined the role of Notch signaling in angiogenesis in a kainic acid-induced mouse model of epilepsy. We show that following seizures, expression of the Notch ligand Jagged1 in the hippocampus is upregulated in astrocytes and levels of activated Notch1 are increased in endothelial cells. Using an in vitro model of angiogenesis, we provide evidence that brain endothelial tube formation is promoted in the presence of astrocytes. Isolated primary brain endothelial cells develop significantly longer vascular sprouts when cultured in the presence of astrocytes. Notch1 signaling is activated in brain endothelial cells cocultured with astrocytes, and astrocytic Jagged1 expression is required for angiogenic enhancement, as shown by the inhibitory effect of Jagged1 small interfering RNA (siRNA) expression in astrocytes on endothelial cell vascular sprouting in vitro. Therapies targeting the Jagged1/Notch1 signaling pathway may therefore be effective in limiting aberrant angiogenesis following status epilepticus.