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Since Scube2 can interact with Sonic hedgehog (Shh) to maintain blood\u2013brain barrier (BBB) integrity via regulating the interaction between brain capillary endothelial cells (ECs) and perivascular astrocytes, and it is also a substrate of MMP\u20102, we hypothesized that the secreted MMP\u20102 could degrade Scube2 and contribute to ischemic BBB disruption. Using an in\u00a0vitro ischemic model of 90\u2010min oxygen\u2013glucose deprivation\/3\u2010h reoxygenation (OGD\/R) and an in\u00a0vivo mouse stroke model of 90\u2010min middle cerebral artery occlusion (MCAO) with 3\u2010h reperfusion, we established an important role of MMP\u20102\u2010mediated Scube2 degradation in early ischemic BBB disruption. Exposure of C8\u2010D1A cells and bEnd.3 cells to OGD\/R increased MMP secretion in both cells, and C8\u2010D1A cells appeared to secrete more MMPs than bEnd.3 cells. Co\u2010IP and double\u2010immunostaining revealed that Scube2 co\u2010localized well with MMP\u20102 in C8\u2010D1A cells and could be pulled down by MMP\u20102 antibodies. In MCAO mice, Scube2 protein showed a drastic reduction in ischemic brain tissue, which was accompanied by suppressed expression of Shh and its downstream molecules. Of note, specific knockdown of astrocytic Scube2 with AAV\u2010shScube2 augmented MCAO\u2010induced Shh suppression and exacerbated BBB leakage and inflammatory reactions in the ischemic brain. Last, incubation of bEnd.3 cells with conditioned medium derived from OGD\u2010treated C8\u2010D1A cells led to a significant inhibition of the Shh pathway in bEnd.3 cells and degradation of VE\u2010cadherin and ZO\u20101. Inhibition of MMP\u20102 with SB\u20103CT or over\u2010expression of Scube2 with plasmids in C8\u2010D1A cells alleviated the above effect of C8\u2010D1A cells\u2010derived conditioned medium. Taken together, our data indicate that ischemia\u2010induced secretion of MMP\u20102 may contribute to early BBB disruption in ischemic stroke via interrupting the shared Scube2\u2010Shh pathway between brain capillary ECs and perivascular astrocytes.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16021-fig-0007-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16021","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T01:54:47Z","timestamp":1703642087000},"page":"1877-1894","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["<scp>MMP<\/scp>\n                    \u20102\u2010mediated Scube2 degradation promotes blood\u2013brain barrier disruption by blocking the interaction between astrocytes and endothelial cells via inhibiting Sonic hedgehog pathway during early cerebral ischemia"],"prefix":"10.1111","volume":"168","author":[{"given":"Tengrui","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital  Shenzhen 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