HIF-1α upregulation-mediated VEGF secretion in contribute to blood brain barrier damage during acute cerebral ischemia

Sun Yanyun; Wang Xiaona; Wang Mengwei; Jin Xinchun

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HIF-1α upregulation-mediated VEGF secretion in contribute to blood brain barrier damage during acute cerebral ischemia

Sun Yanyun #,Wang Xiaona,Wang Mengwei,Jin Xinchun *

Institute of Neuroscience, Soochow University, Suzhou, 215123

*Correspondence author

#Submitted by

Subject:

Funding: Doctoral New Teacher researching Fundation of the department of education（No.No. K521507713）

Opened online: 6 December 2016

Accepted by: none

Citation: Sun Yanyun,Wang Xiaona,Wang Mengwei.HIF-1α upregulation-mediated VEGF secretion in contribute to blood brain barrier damage during acute cerebral ischemia[OL]. [ 6 December 2016] http://en.paper.edu.cn/en_releasepaper/content/4712149

Although disruption of the blood brain barrier (BBB) is an antecedent event to intracerebral hemorrhage (ICH) in ischemic stroke, the mechanism of acute BBB disruption within the thrombolytic time window remains less well known. Since hypoxia-inducible factor-1 alpha (HIF-1α) was discovered as a mater regulator in hypoxia, we sought to test our hypothesis that HIF-1α and its downstream vascular endothelial growth factor (VEGF) triggered BBB damage. Using in vivo rat middle cerebral artery occlusion (MCAO) and in vitro oxygen glucose deprivation (OGD) models, our results showed that pretreatment with HIF-1α inhibitor YC-1 significantly inhibited the upregulation of HIF-1α protein and VEGF mRNA as well as occludin degradation and BBB damage in ventral striatum and preoptic area induced by 2-h MCAO. Increased HIF-1α was shown to colocalize with neurons but not astrocytes. Of note, cell study showed that HIF-1α inhibition with YC-1 or siRNA significantly prevented VEGF secretion of neuron promoted by 2-h OGD. Taken together, acute cerebral ischemia led to HIF-1α upregualtion and activated the neurons to secret VEGF, which eventually induced occludin degradation and BBB disruption. These findings may provide new ideas and strategies to extend the time window of thrombolysis and reduce cerebral hemorrhage.

Keywords:cerebral ischemia; HIF-1α; VEGF; blood brain barrier; tight junction proteins

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