Abstract
BackgroundBlood-brain barrier impairment is a major indicator of endothelial dysfunction in diabetes. Studies showed that endothelial progenitor cell (EPC) transplantation promoted angiogenesis and improved function recovery after hind limb ischemia in diabetic mice. The effect of EPC transplantation on blood-brain barrier integrity after cerebral ischemia in diabetic animals is unknown. The aim of this study is to explore the effect of EPC transplantation on the integrity of the blood-brain barrier after cerebral ischemia in diabetic mice.MethodsEPCs were isolated by density gradient centrifugation and characterized by flow cytometry and immunostaining. Diabetes was induced in adult male C57BL/6 mice by a single injection of streptozotocin at 4 weeks before surgery. Diabetic mice underwent 90-minute transient middle cerebral artery occlusion surgery and received 1 × 106 EPCs transplantation immediately after reperfusion. Brain infarct volume, blood-brain barrier permeability, tight junction protein expression, and hypoxia inducible factor-1α (HIF-1α) mRNA level were examined after treatment.ResultsWe demonstrated that neurological deficits were attenuated and brain infarct volume was reduced in EPC-transplanted diabetic mice after transient cerebral ischemia compared to the controls (p < 0.05). Blood-brain barrier leakage and tight junction protein degradation were reduced in EPC-transplanted mice (p <0.05). EPCs upregulated HIF-1α expression while HIF-1α inhibitor PX-478 abolished the beneficial effect of EPCs.ConclusionsWe conclude that EPCs protected blood-brain barrier integrity after focal ischemia in diabetic mice through upregulation of HIF-1α signaling.
Highlights
Blood-brain barrier impairment is a major indicator of endothelial dysfunction in diabetes
We investigated the role of hypoxia inducible factor-1α (HIF-1α) in endothelial progenitor cell (EPC)-treated diabetic mice after transient MCAO (tMCAO), and the diabetic mice were divided into PBStreated, EPC-treated, HIF-1α inhibitor PX-478-treated and EPC plus PX-478 co-treated groups
We found that the mRNA level of HIF-1α was upregulated after tMCAO, and it was further enhanced in the EPC-treated mice than that in the phosphate-buffered saline (PBS)-treated mice (p < 0.05, Fig. 5A)
Summary
Blood-brain barrier impairment is a major indicator of endothelial dysfunction in diabetes. Studies showed that endothelial progenitor cell (EPC) transplantation promoted angiogenesis and improved function recovery after hind limb ischemia in diabetic mice. The effect of EPC transplantation on blood-brain barrier integrity after cerebral ischemia in diabetic animals is unknown. The aim of this study is to explore the effect of EPC transplantation on the integrity of the blood-brain barrier after cerebral ischemia in diabetic mice. Diabetes is an independent risk factor for ischemic stroke [1]. A recent clinical study reported that acute ischemic stroke patients with diabetes have a higher risk for symptomatic intracerebral hemorrhage following thrombolytic therapy. Mesenchymal stem cell (MSC) transplantation improved functional recovery after ischemic stroke in clinical trials in humans [8]. Studies showed that MSC therapy for ischemic stroke in diabetic
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