Ischemic neurons activate astrocytes to disrupt endothelial barrier via increasing VEGF expression. (6th December 2013)

• Record Type: Journal Article
• Authors: Li, Ying‐Na; Pan, Rong; Qin, Xu‐Jun; Yang, Wei‐Lin; Qi, Zhifeng; Liu, Wenlan; Liu, Ke Jian
• Is Part Of: Journal of neurochemistry. Volume 129:Number 1(2014:Apr.)
• Page Start: 120
• Page End: 129
• Publication Date: 2013-12-06
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12611
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12611-abs-0001"> <title>Abstract</title> <p>Blood–brain barrier (BBB) disruption occurring within the first few hours of ischemic stroke onset is closely associated with hemorrhagic transformation following thrombolytic therapy. However, the mechanism of this acute BBB disruption remains unclear. In the neurovascular unit, neurons do not have direct contact with the endothelial barrier; however, they are highly sensitive and vulnerable to ischemic injury, and may act as the initiator for disrupting BBB when cerebral ischemia occurs. Herein, we employed oxygen–glucose deprivation (OGD) and an <italic>in vitro</italic> BBB system consisting of brain microvascular cells and astrocytes to test this hypothesis. Neurons (CATH.a cells) were exposed to OGD for 3‐h before co‐culturing with endothelial monolayer (bEnd 3 cells), or endothelial cells plus astrocytes (C8‐D1A cells). Incubation of OGD‐treated neurons with endothelial monolayer alone did not increase endothelial permeability. However, when astrocytes were present, the endothelial permeability was significantly increased, which was accompanied by loss of occludin and claudin‐5 proteins as well as increased vascular endothelial growth factor (VEGF) secretion into the conditioned medium. Importantly, all these changes were abolished when VEGF was knocked down in astrocytes by siRNA. Our findings suggest that ischemic neurons activate astrocytes to increase VEGF production, which in turn induces endothelial barrier disruption. <boxed-text content-type="graphic" id="jnc12611-blkfxd-0001" position="anchor" orientation="portrait"><graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pgg4vnwvghz" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /></boxed-text></p> <p>Little is known about the contribution of neurons to blood–brain barrier (BBB) injury following cerebral ischemia. Using co‐culture model of neurons, astrocytes and endothelial cells, we found that ischemic neurons activated astrocytes to increase vascular endothelial growth factor (VEGF) secretion that in turns acted on tight junction proteins to increase BBB permeability. These results clearly suggest an important role of neurons in ischemic BBB damage.</p> </abstract>