title: Recombinant human sonic hedgehog protein regulates the expression of ZO-1 and occludin by activating angiopoietin-1 in stroke damage.
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.
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yuan-peng
authors.initials: YP
authors.lastname: Xia
authors.forename: Quan-wei
authors.initials: QW
authors.lastname: He
authors.forename: Ya-nan
authors.initials: YN
authors.lastname: Li
authors.forename: Sheng-cai
authors.initials: SC
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Huang
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Meng-die
authors.initials: MD
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Mao
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D062793:Occludin / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D020521:Stroke / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015854:Up-Regulation; D062826:Zonula Occludens-1 Protein / Q000096:biosynthesis*
chemical_list: D042683:Angiopoietin-1; C467629:Angpt1 protein, rat; D053823:Hedgehog Proteins; D062793:Occludin; C568987:Ocln protein, rat; D011994:Recombinant Proteins; C509239:SHH protein, human; D062826:Zonula Occludens-1 Protein
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