Abstract
This study examines the regulating effect of Sonic Hedgehog (Shh) on the permeability of the blood-brain barrier (BBB) in cerebral ischemia. By employing permanent middle cerebral artery occlusion (pMCAO) model, we find that Shh significantly decreases brain edema and preserves BBB permeability. Moreover, Shh increases zonula occludens-1 (ZO-1), occludin and angiopiotetin-1 (Ang-1) expression in the ischemic penumbra. Blockage of Shh with cyclopamine abolishes the effects of Shh on brain edema, BBB permeability and ZO-1, occludin, Ang-1 expression. Primary brain microvessel endothelial cells (BMECs) and astrocytes were pre-treated with Shh, cyclopamine, Ang-1-neutralizing antibody, and subjected to oxygen-glucose deprivation (OGD). Results show that the Ang-1 protein level in the culture medium of Shh-treated astrocytes is significantly higher. Shh also increased ZO-1, occludin and Ang-1 expression in BMECs, while cyclopamine and Ang-1-neutralizing antibody inhibited the effects of Shh on the ZO-1 and occludin expression, respectively. This study suggests that, under ischemic insults, Shh triggers Ang-1 production predominantly in astrocytes, and the secreted Ang-1 acts on BMECs, thereby upregulating ZO-1 and occludin to repair the tight junction and ameliorate the brain edema and BBB leakage.
Highlights
Stroke leads to the disruption of the blood-brain barrier (BBB), which increases the permeability of the brain microvasculature and eventually results in brain edema [1]
A recent study showed that the Sonic hedgehog (Shh), a glycoprotein secreted by astrocytes, interacts with cerebral endothelial cells to ensure the integrity of BBB by modulating the expression of Zonula occludens-1 (ZO-1), occludin, claudin-5 [4]
Administration of Shh significantly increased the mRNA expression level of ZO-1 (3.3260.38, 4.9260.84, 7.5861.68, *P,0.01 vs. the PBS group) and occludin (3.0360.46, 5.0860.71, 7.7261.09, *P,0.01 vs. the PBS group) after the treatment as compared with the permanent middle cerebral artery occlusion (pMCAO) plus PBS group, and the effects could be reversed by cyclopamine (ZO1:1.5060.68, 2.7460.34, 4.6360.85, #P,0.01 vs. the Shh group; occludin: 1.7560.38, 2.6060.81, 4.5761.58, #P,0.01 vs. the Shh group)
Summary
Stroke leads to the disruption of the blood-brain barrier (BBB), which increases the permeability of the brain microvasculature and eventually results in brain edema [1]. TJs reduce the permeability of cerebral vessels by restricting the free molecular exchange between blood and brain tissues, and structural damage of TJs could cause the leakage of BBB and brain edema [2]. Zonula occludens-1 (ZO-1), occludin, claudin-5 proteins are important components of TJs structure and are implicated in the maintenance of integrity of TJs [3]. Understanding of the mechanism by which the integrity of TJs is maintained and the ZO-1, occludin, claudin-5 expression is regulated has potential implication for the treatment of cerebral ischemia. A recent study showed that the Sonic hedgehog (Shh), a glycoprotein secreted by astrocytes, interacts with cerebral endothelial cells to ensure the integrity of BBB by modulating the expression of ZO-1, occludin, claudin-5 [4]. The underlying mechanism by which Shh modulates the BBB to relieve brain edema in brain ischemia remains poorly understood
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