Inhibition of HIF-1α Reduced Blood Brain Barrier Damage by Regulating MMP-2 and VEGF During Acute Cerebral Ischemia

• Published in: Frontiers in cellular neuroscience Vol. 12; p. 288
• Main Authors: Shen, Yufei, Gu, Jingxia, Liu, Ziyun, Xu, Congying, Qian, Shuxia, Zhang, Xiaoling, Zhou, Beiqun, Guan, Qiaobing, Sun, Yanyun, Wang, Yanping, Jin, Xinchun
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 04.09.2018; Frontiers Media S.A
• Subjects: Adrenergic receptors; Astrocytes; Binding sites; Blood-brain barrier; Brain; Brain injury; Cardiovascular system; Carotid arteries; Cerebral blood flow; Dextran; Gelatinase A; Hemorrhage; HIF-1α; Hospitals; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; Ischemia; ischemia stroke; Kinases; Laboratory animals; Localization; Matrix metalloproteinase; Membrane permeability; Metalloproteinase; Neuroscience; Permeability; Rhodamine; Stroke; t-Plasminogen activator; Thrombolysis; Vascular endothelial growth factor; Veins & arteries; United States > US; China; blood brain barrier; matrix metalloproteinase; HIF-1α; vascular endothelial growth factor; ischemia stroke
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2018.00288

Increase of blood brain barrier (BBB) permeability after acute ischemia stroke is a predictor to intracerebral hemorrhage transformation (HT) for tissue plasminogen activator (tPA) thrombolysis and post-endovascular treatment. Previous studies showed that 2-h ischemia induced damage of BBB integrity and matrix metalloproteinase-2 (MMP-2) made major contribution to this disruption. A recent study showed that blocking β2-adrenergic receptor (β2-AR) alleviated ischemia-induced BBB injury by reducing hypoxia-inducible factor-1 alpha (HIF-1α) level. In this study, we sought to investigate the interaction of HIF-1α with MMP-2 and vascular endothelial growth factor (VEGF) in BBB injury after acute ischemia stroke. Rat suture middle cerebral artery occlusion (MCAO) model was used to mimic ischemia condition. Our results showed that ischemia produced BBB damage and MMP-2/9 upregulation was colocalized with Rhodamine-dextran leakage. Pretreatment with YC-1, a HIF-1α inhibitor, alleviated 2-h ischemia-induced BBB injury significantly accompanied by decrease of MMP-2 upregulation. In addition, YC-1 also prevented VEGF-induced BBB damage. Of note, VEGF was shown to be colocalized with neurons but not astrocytes. Taken together, BBB damage was reduced by inhibition of interaction of HIF-1α with MMP-2 and VEGF during acute cerebral ischemia. These findings provide mechanisms underlying BBB damage after acute ischemia stroke and may help reduce thrombolysis- and post-endovascular treatment-related cerebral hemorrhage.