Activation of Frizzled-7 attenuates blood–brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in mice
Abstract Background Destruction of blood–brain barrier (BBB) is one of the main mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Frizzled-7 is a key protein expressed on the surface of endothelial cells that controls vascular permeability through the Wnt-canonical pat...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-09-01
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| Series: | Fluids and Barriers of the CNS |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12987-021-00278-9 |
| _version_ | 1818934977868333056 |
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| author | Wei He Qin Lu Prativa Sherchan Lei Huang Xin Hu John H. Zhang Haibin Dai Jiping Tang |
| author_facet | Wei He Qin Lu Prativa Sherchan Lei Huang Xin Hu John H. Zhang Haibin Dai Jiping Tang |
| author_sort | Wei He |
| collection | DOAJ |
| description | Abstract Background Destruction of blood–brain barrier (BBB) is one of the main mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Frizzled-7 is a key protein expressed on the surface of endothelial cells that controls vascular permeability through the Wnt-canonical pathway involving WNT1-inducible signaling pathway protein 1 (WISPI). This study aimed to investigate the role of Frizzled-7 signaling in BBB preservation after ICH in mice. Methods Adult CD1 mice were subjected to sham surgery or collagenase-induced ICH. Frizzled-7 activation or knockdown was performed by administration of Clustered Regularly Interspaced Palindromic Repeats (CRISPR) by intracerebroventricular injection at 48 h before ICH induction. WISP1 activation or WISP1 knockdown was performed to evaluate the underlying signaling pathway. Post-ICH assessments included neurobehavior, brain edema, BBB permeability, hemoglobin level, western blot and immunofluorescence. Results The brain expressions of Frizzled-7 and WISP1 significantly increased post-ICH. Frizzled-7 was expressed in endothelial cells, astrocytes, and neurons after ICH. Activation of Frizzled-7 significantly improved neurological function, reduced brain water content and attenuated BBB permeability to large molecular weight substances after ICH. Whereas, knockdown of Frizzled-7 worsened neurological function and brain edema after ICH. Activation of Frizzled-7 significantly increased the expressions of Dvl, β-Catenin, WISP1, VE-Cadherin, Claudin-5, ZO-1 and reduced the expression of phospho-β-Catenin. WISP1 knockdown abolished the effects of Frizzled-7 activation on the expressions of VE-Cadherin, Claudin-5 and ZO-1 at 24 h after ICH. Conclusions Frizzled-7 activation potentially attenuated BBB permeability and improved neurological deficits after ICH through Dvl/β-Catenin/WISP1 pathway. Frizzled-7 may be a potential target for the development of ICH therapeutic drugs. |
| first_indexed | 2024-12-20T05:12:51Z |
| format | Article |
| id | doaj.art-84b1fd30526f417ab9e181306335abb1 |
| institution | Directory Open Access Journal |
| issn | 2045-8118 |
| language | English |
| last_indexed | 2024-12-20T05:12:51Z |
| publishDate | 2021-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj.art-84b1fd30526f417ab9e181306335abb12022-12-21T19:52:14ZengBMCFluids and Barriers of the CNS2045-81182021-09-0118111410.1186/s12987-021-00278-9Activation of Frizzled-7 attenuates blood–brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in miceWei He0Qin Lu1Prativa Sherchan2Lei Huang3Xin Hu4John H. Zhang5Haibin Dai6Jiping Tang7Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of MedicineDepartment of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of MedicineDepartment of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of MedicineDepartment of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of MedicineDepartment of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of MedicineDepartment of Pharmacy, Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of MedicineAbstract Background Destruction of blood–brain barrier (BBB) is one of the main mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Frizzled-7 is a key protein expressed on the surface of endothelial cells that controls vascular permeability through the Wnt-canonical pathway involving WNT1-inducible signaling pathway protein 1 (WISPI). This study aimed to investigate the role of Frizzled-7 signaling in BBB preservation after ICH in mice. Methods Adult CD1 mice were subjected to sham surgery or collagenase-induced ICH. Frizzled-7 activation or knockdown was performed by administration of Clustered Regularly Interspaced Palindromic Repeats (CRISPR) by intracerebroventricular injection at 48 h before ICH induction. WISP1 activation or WISP1 knockdown was performed to evaluate the underlying signaling pathway. Post-ICH assessments included neurobehavior, brain edema, BBB permeability, hemoglobin level, western blot and immunofluorescence. Results The brain expressions of Frizzled-7 and WISP1 significantly increased post-ICH. Frizzled-7 was expressed in endothelial cells, astrocytes, and neurons after ICH. Activation of Frizzled-7 significantly improved neurological function, reduced brain water content and attenuated BBB permeability to large molecular weight substances after ICH. Whereas, knockdown of Frizzled-7 worsened neurological function and brain edema after ICH. Activation of Frizzled-7 significantly increased the expressions of Dvl, β-Catenin, WISP1, VE-Cadherin, Claudin-5, ZO-1 and reduced the expression of phospho-β-Catenin. WISP1 knockdown abolished the effects of Frizzled-7 activation on the expressions of VE-Cadherin, Claudin-5 and ZO-1 at 24 h after ICH. Conclusions Frizzled-7 activation potentially attenuated BBB permeability and improved neurological deficits after ICH through Dvl/β-Catenin/WISP1 pathway. Frizzled-7 may be a potential target for the development of ICH therapeutic drugs.https://doi.org/10.1186/s12987-021-00278-9Intracerebral hemorrhageBlood–brain barrierFrizzled-7Dvlβ-CateninWISP1 |
| spellingShingle | Wei He Qin Lu Prativa Sherchan Lei Huang Xin Hu John H. Zhang Haibin Dai Jiping Tang Activation of Frizzled-7 attenuates blood–brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in mice Fluids and Barriers of the CNS Intracerebral hemorrhage Blood–brain barrier Frizzled-7 Dvl β-Catenin WISP1 |
| title | Activation of Frizzled-7 attenuates blood–brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in mice |
| title_full | Activation of Frizzled-7 attenuates blood–brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in mice |
| title_fullStr | Activation of Frizzled-7 attenuates blood–brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in mice |
| title_full_unstemmed | Activation of Frizzled-7 attenuates blood–brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in mice |
| title_short | Activation of Frizzled-7 attenuates blood–brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in mice |
| title_sort | activation of frizzled 7 attenuates blood brain barrier disruption through dvl β catenin wisp1 signaling pathway after intracerebral hemorrhage in mice |
| topic | Intracerebral hemorrhage Blood–brain barrier Frizzled-7 Dvl β-Catenin WISP1 |
| url | https://doi.org/10.1186/s12987-021-00278-9 |
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