PMID- 36028880 OWN - NLM STAT- MEDLINE DCOM- 20220830 LR - 20220830 IS - 2045-8118 (Electronic) IS - 2045-8118 (Linking) VI - 19 IP - 1 DP - 2022 Aug 26 TI - A transcriptomic analysis of cerebral microvessels reveals the involvement of Notch1 signaling in endothelial mitochondrial-dysfunction-dependent BBB disruption. PG - 64 LID - 10.1186/s12987-022-00363-7 [doi] LID - 64 AB - 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. CI - (c) 2022. The Author(s). FAU - Lee, Min Joung AU - Lee MJ AD - Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea. FAU - Zhu, Jiebo AU - Zhu J AD - Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea. AD - Brain Korea 21 FOUR Project for Medical Science, Chungnam National University, Daejeon, 35015, Republic of Korea. AD - Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea. FAU - An, Jong Hun AU - An JH AD - Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea. AD - Brain Korea 21 FOUR Project for Medical Science, Chungnam National University, Daejeon, 35015, Republic of Korea. AD - Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea. FAU - Lee, Seong Eun AU - Lee SE AD - Research Center for Endocrine and Metabolic Disease, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea. AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University School of Medicine, Deajeon, 35015, Republic of Korea. FAU - Kim, Tae Yeon AU - Kim TY AD - Bio-Synergy Research Center, Daejeon, 34141, Republic of Korea. FAU - Oh, Eungseok AU - Oh E AD - Department of Neurology, Chungnam National University Hospital, Daejeon, 35015, Republic of Korea. FAU - Kang, Yea Eun AU - Kang YE AD - Research Center for Endocrine and Metabolic Disease, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea. yeeuni220@cnuh.co.kr. AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University School of Medicine, Deajeon, 35015, Republic of Korea. yeeuni220@cnuh.co.kr. FAU - Chung, Woosuk AU - Chung W AD - Brain Korea 21 FOUR Project for Medical Science, Chungnam National University, Daejeon, 35015, Republic of Korea. woosuk119@cnu.ac.kr. AD - Department of Anesthesiology and Pain Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea. woosuk119@cnu.ac.kr. AD - Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, Daejeon, 35015, Republic of Korea. woosuk119@cnu.ac.kr. FAU - Heo, Jun Young AU - Heo JY AD - Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea. junyoung3@gmail.com. AD - Brain Korea 21 FOUR Project for Medical Science, Chungnam National University, Daejeon, 35015, Republic of Korea. junyoung3@gmail.com. AD - Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea. junyoung3@gmail.com. LA - eng GR - 2020R1A6A3A01097081/by Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Education/ GR - 2022R1A2C2006269/the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (MSIP)/ GR - 2017R1A5A2015385/the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (MSIP)/ GR - 2019M3E5D1A02068575/This research was funded by the Bio & Medical Technology Development Program of the National Research Foundation (NRF)/ GR - HR20C0025/a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare/ PT - Journal Article DEP - 20220826 PL - England TA - Fluids Barriers CNS JT - Fluids and barriers of the CNS JID - 101553157 SB - IM MH - Animals MH - *Blood-Brain Barrier MH - *Brain Injuries MH - Cerebral Hemorrhage MH - Disease Models, Animal MH - Endothelial Cells MH - Gene Expression Profiling MH - Mice MH - Microvessels MH - Mitochondria MH - Signal Transduction MH - Transcriptome PMC - PMC9414148 OTO - NOTNLM OT - Blood-brain barrier OT - Endothelial cell OT - Intracellular stroke OT - Mitochondria COIS- The authors declare that they have no competing interests. EDAT- 2022/08/27 06:00 MHDA- 2022/08/31 06:00 PMCR- 2022/08/26 CRDT- 2022/08/26 23:44 PHST- 2022/06/30 00:00 [received] PHST- 2022/08/10 00:00 [accepted] PHST- 2022/08/26 23:44 [entrez] PHST- 2022/08/27 06:00 [pubmed] PHST- 2022/08/31 06:00 [medline] PHST- 2022/08/26 00:00 [pmc-release] AID - 10.1186/s12987-022-00363-7 [pii] AID - 363 [pii] AID - 10.1186/s12987-022-00363-7 [doi] PST - epublish SO - Fluids Barriers CNS. 2022 Aug 26;19(1):64. doi: 10.1186/s12987-022-00363-7.