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

Abstract

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.

Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences

“…HIF-1α upregulation after diabetic stroke has also been seen to play a role in the breakdown of the BBB. Knockout of HIF-1α ameliorated BBB permeability as well as tight junction disruption (263). A downstream target of HIF-1 is VEGF.…”

Acute cardiac support with intravenous milrinone promotes recovery from early brain injury in a murine model of severe subarachnoid haemorrhage

“…In contrast, the therapeutic efficacy of MIL infusion with and without intravenous sedation in patients following SAH has been established in several clinical settings including SAH . Thus, the timing, severity, and sustainability of HIF‐1α upregulation and its downstream transcriptional effects may also be pursued in translational studies using genetically modified mice to identify more promising preventive or prophylactic interventions against post‐SAH DCI.…”

“…Indeed, several in vitro studies using a rat model reported discrepant findings, which indicated that HIF inhibition per se has been associated with improved blood-brain barrier 34,35 In contrast, the therapeutic efficacy of MIL infusion with and without intravenous sedation in patients following SAH has been established in several clinical settings including SAH. 6,11,14,[29][30][31][32][33] Thus, the timing, severity, and sustainability of HIF-1α upregulation and its downstream transcriptional effects may also be pursued in translational studies using genetically modified mice [36][37][38] to identify more promising preventive or prophylactic interventions against post-SAH DCI.…”

Hyperglycemia aggravates decreases of PEA-15 and its two phosphorylated forms in cerebral ischemia

“…High blood glucose levels are associated with both degree of disability and infarct size in human and in rodent models of stroke [3, 17, 24]. Diabetes enhances the development of stroke and neuronal destruction by activating cortical apoptotic activity following cerebral ischemia [17, 34, 35]. Diabetes aggravates cerebral stroke and its poor outcomes after focal cerebral ischemia [17, 24].…”

“…Thus, hyperglycemia is accepted as risk factors that appear to perform critical roles in the severity of stroke. Hyperglycemia aggravates cerebral damage, increases morbidity and mortality, and worse clinical outcomes [4, 20, 34, 35]. Inflammation response is one of the pathological mechanisms in diabetes mellitus.…”