Role of Hypoxia Inducible Factor 1 in Hyperglycemia-Exacerbated Blood-Brain Barrier Disruption in Ischemic Stroke

• Hyperglycemia enhanced HIF-1α and VEGF expression in ischemic brain microvessels.
• Suppressing endothelial HIF-1α activity ameliorated BBB leakage and brain injury.
• Correcting blood glucose abolished HIF-1α upregulation in brain microvessels and reduced BBB permeability.

Diabetes is a major stroke risk factor and is associated with poor functional recovery after stroke. Accumulating evidence indicates that the worsened outcomes may be due to hyperglycemia-induced cerebral vascular complications, especially disruption of the blood-brain barrier (BBB). The present study tested a hypothesis that the activation of hypoxia inducible factor-1 (HIF-1) was involved in hyperglycemia-aggravated BBB disruption in an ischemic stroke model. Non-diabetic control and Streptozotocin-induced type I diabetic mice were subjected to 90 min transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Our results demonstrated that hyperglycemia induced higher expression of HIF-1α and vascular endothelial growth factor (VEGF) in brain microvessels after MCAO/reperfusion. Diabetic mice showed exacerbated BBB damage and tight junction disruption, increased infarct volume as well as worsened neurological deficits. Furthermore, suppressing HIF-1 activity by specific knock-out endothelial HIF-1α ameliorated BBB leakage and brain infarction in diabetic animals. Moreover, glycemic control by insulin abolished HIF-1α up-regulation in diabetic animals and reduced BBB permeability and brain infarction. These findings strongly indicate that HIF-1 plays an important role in hyperglycemia-induced exacerbation of BBB disruption in ischemic stroke. Endothelial HIF-1 inhibition warrants further investigation as a therapeutic target for the treatment of stroke patients with diabetes.