Oxygen-Glucose Deprivation/Reoxygenation-Induced Barrier Disruption at the Human Blood-Brain Barrier is Partially Mediated Through the HIF-1 Pathway.

Abstract

The blood-brain barrier (BBB) plays an important role in brain homeostasis. Hypoxia/ischemia constitutes an important stress factor involved in several neurological disorders by inducing the disruption of the BBB, ultimately leading to cerebral edema formation. Yet, our current understanding of the cellular and molecular mechanisms underlying the BBB disruption following cerebral hypoxia/ischemia remains limited. Stem cell-based models of the human BBB present some potentials to address such issues. Yet, such models have not been validated in regard of its ability to respond to hypoxia/ischemia as existing models. In this study, we investigated the cellular response of two iPSC-derived brain microvascular endothelial cell (BMEC) monolayers to respond to oxygen-glucose deprivation (OGD) stress, using two induced pluripotent stem cells (iPSC) lines. iPSC-derived BMECs responded to prolonged (24h) and acute (6h) OGD by showing a decrease in the barrier function and a decrease in tight junction complexes. Such iPSC-derived BMECs responded to OGD stress via a partial activation of the HIF-1 pathway, whereas treatment with anti-angiogenic pharmacological inhibitors (sorafenib, sunitinib) during reoxygenation worsened the barrier function. Taken together, our results suggest such models can respond to hypoxia/ischemia similarly to existing in vitro models and support the possible use of this model as a screening platform for identifying novel drug candidates capable to restore the barrier function following hypoxic/ischemic injury.