A transcriptomic analysis of cerebral microvessels reveals the involvement of Notch1 signaling in endothelial mitochondrial-dysfunction-dependent BBB disruption
Abstract Background Endothelial cells (ECs) in cerebral vessels are considered the primary targets in acute hemorrhagic brain injuries. EC dysfunction can aggravate neuronal injuries by causing secondary inflammatory responses and blood–brain barrier (BBB) disruption. Previous studies have reported...
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Fluids and Barriers of the CNS |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12987-022-00363-7 |
| _version_ | 1811281912179720192 |
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| author | Min Joung Lee Jiebo Zhu Jong Hun An Seong Eun Lee Tae Yeon Kim Eungseok Oh Yea Eun Kang Woosuk Chung Jun Young Heo |
| author_facet | Min Joung Lee Jiebo Zhu Jong Hun An Seong Eun Lee Tae Yeon Kim Eungseok Oh Yea Eun Kang Woosuk Chung Jun Young Heo |
| author_sort | Min Joung Lee |
| collection | DOAJ |
| description | Abstract Background Endothelial cells (ECs) in cerebral vessels are considered the primary targets in acute hemorrhagic brain injuries. EC dysfunction can aggravate neuronal injuries by causing secondary inflammatory responses and blood–brain barrier (BBB) disruption. Previous studies have reported that enhancement of mitochondrial function within ECs may reduce BBB disruption and decrease the severity of acute brain injuries. However, the molecular signaling pathways through which enhanced EC mitochondrial function is enhanced to exert this BBB protective effect have not been fully elucidated. Methods To identify signaling pathways involved in linking EC-specific mitochondrial dysfunction and BBB disruption, we first performed RNA sequencing using isolated cerebral vessels from TEKCRIF1 KO mice, a mouse strain that displays EC-specific mitochondrial dysfunction. After identification, we assessed the significance of candidate signaling pathways using an intracerebral hemorrhage (ICH) mouse model. BBB integrity was assessed using an IgG leakage assay, and symptomatic changes were evaluated using behavioral assays. Results Transcriptome analyses of the TEKCRIF1 KO mouse revealed significant changes in Notch1 signaling, a pathway intimately involved in BBB maintenance. We also observed a decrease in Notch1 signaling and expression of the mitochondrial oxidative phosphorylation (OxPhos) complex in the ICH mouse model, which also exhibits BBB disruption. To further assess the function of Notch1 signaling in relation to BBB disruption, we injected ICH model mice with adropin, a protein that interacts with the Notch1 ligand NB-3 and activates Notch1 signaling. We found that adropin prevented BBB disruption and reduced the extent (area) of the injury compared with that in vehicle controls, in association with alteration of mitochondrial function. Conclusion These results suggest that the Notch1 signaling pathway acts as an upstream regulator of DEGs and can be a target to regulate the changes involved with endothelial mitochondrial dysfunction-dependent BBB disruption. Thus, treatment methods that activate Notch1 may be beneficial in acute brain injuries by protecting BBB integrity. |
| first_indexed | 2024-04-13T01:42:07Z |
| format | Article |
| id | doaj.art-9ef614e6457840c1b42b2e37eb2bb129 |
| institution | Directory Open Access Journal |
| issn | 2045-8118 |
| language | English |
| last_indexed | 2024-04-13T01:42:07Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj.art-9ef614e6457840c1b42b2e37eb2bb1292022-12-22T03:08:08ZengBMCFluids and Barriers of the CNS2045-81182022-08-0119111510.1186/s12987-022-00363-7A transcriptomic analysis of cerebral microvessels reveals the involvement of Notch1 signaling in endothelial mitochondrial-dysfunction-dependent BBB disruptionMin Joung Lee0Jiebo Zhu1Jong Hun An2Seong Eun Lee3Tae Yeon Kim4Eungseok Oh5Yea Eun Kang6Woosuk Chung7Jun Young Heo8Department of Biochemistry, Chungnam National University School of MedicineDepartment of Biochemistry, Chungnam National University School of MedicineDepartment of Biochemistry, Chungnam National University School of MedicineResearch Center for Endocrine and Metabolic Disease, College of Medicine, Chungnam National UniversityBio-Synergy Research CenterDepartment of Neurology, Chungnam National University HospitalResearch Center for Endocrine and Metabolic Disease, College of Medicine, Chungnam National UniversityBrain Korea 21 FOUR Project for Medical Science, Chungnam National UniversityDepartment of Biochemistry, Chungnam National University School of MedicineAbstract Background Endothelial cells (ECs) in cerebral vessels are considered the primary targets in acute hemorrhagic brain injuries. EC dysfunction can aggravate neuronal injuries by causing secondary inflammatory responses and blood–brain barrier (BBB) disruption. Previous studies have reported that enhancement of mitochondrial function within ECs may reduce BBB disruption and decrease the severity of acute brain injuries. However, the molecular signaling pathways through which enhanced EC mitochondrial function is enhanced to exert this BBB protective effect have not been fully elucidated. Methods To identify signaling pathways involved in linking EC-specific mitochondrial dysfunction and BBB disruption, we first performed RNA sequencing using isolated cerebral vessels from TEKCRIF1 KO mice, a mouse strain that displays EC-specific mitochondrial dysfunction. After identification, we assessed the significance of candidate signaling pathways using an intracerebral hemorrhage (ICH) mouse model. BBB integrity was assessed using an IgG leakage assay, and symptomatic changes were evaluated using behavioral assays. Results Transcriptome analyses of the TEKCRIF1 KO mouse revealed significant changes in Notch1 signaling, a pathway intimately involved in BBB maintenance. We also observed a decrease in Notch1 signaling and expression of the mitochondrial oxidative phosphorylation (OxPhos) complex in the ICH mouse model, which also exhibits BBB disruption. To further assess the function of Notch1 signaling in relation to BBB disruption, we injected ICH model mice with adropin, a protein that interacts with the Notch1 ligand NB-3 and activates Notch1 signaling. We found that adropin prevented BBB disruption and reduced the extent (area) of the injury compared with that in vehicle controls, in association with alteration of mitochondrial function. Conclusion These results suggest that the Notch1 signaling pathway acts as an upstream regulator of DEGs and can be a target to regulate the changes involved with endothelial mitochondrial dysfunction-dependent BBB disruption. Thus, treatment methods that activate Notch1 may be beneficial in acute brain injuries by protecting BBB integrity.https://doi.org/10.1186/s12987-022-00363-7Blood–brain barrierEndothelial cellMitochondriaIntracellular stroke |
| spellingShingle | Min Joung Lee Jiebo Zhu Jong Hun An Seong Eun Lee Tae Yeon Kim Eungseok Oh Yea Eun Kang Woosuk Chung Jun Young Heo A transcriptomic analysis of cerebral microvessels reveals the involvement of Notch1 signaling in endothelial mitochondrial-dysfunction-dependent BBB disruption Fluids and Barriers of the CNS Blood–brain barrier Endothelial cell Mitochondria Intracellular stroke |
| title | A transcriptomic analysis of cerebral microvessels reveals the involvement of Notch1 signaling in endothelial mitochondrial-dysfunction-dependent BBB disruption |
| title_full | A transcriptomic analysis of cerebral microvessels reveals the involvement of Notch1 signaling in endothelial mitochondrial-dysfunction-dependent BBB disruption |
| title_fullStr | A transcriptomic analysis of cerebral microvessels reveals the involvement of Notch1 signaling in endothelial mitochondrial-dysfunction-dependent BBB disruption |
| title_full_unstemmed | A transcriptomic analysis of cerebral microvessels reveals the involvement of Notch1 signaling in endothelial mitochondrial-dysfunction-dependent BBB disruption |
| title_short | A transcriptomic analysis of cerebral microvessels reveals the involvement of Notch1 signaling in endothelial mitochondrial-dysfunction-dependent BBB disruption |
| title_sort | transcriptomic analysis of cerebral microvessels reveals the involvement of notch1 signaling in endothelial mitochondrial dysfunction dependent bbb disruption |
| topic | Blood–brain barrier Endothelial cell Mitochondria Intracellular stroke |
| url | https://doi.org/10.1186/s12987-022-00363-7 |
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