title: Notch-1 signaling regulates astrocytic proliferation and activation after hypoxia exposure.
abstract: Activation of astrocyte has been implicated in the neonatal hypoxic brain injury. However, the mechanisms that control astrocytic activation and astrogliosis formation remain unknown. Here, we found that Notch-1 is upregulated and activated by hypoxia in astrocytes as confirmed by an increase in NICD and Hes-1 expression. Remarkably, blockade of Notch-1 signaling with the specific inhibitor DAPT suppressed astrocytic proliferation. In addition, both expression and secretion of inflammatory factor IL-1β was inhibited in DAPT-pretreated astrocytes, while no significant change in TNF-α expression was detected. Most interestingly, GFAP and VEGF expression was suppressed by DAPT pretreatment in hypoxic astrocytes and further confirmed in neonatal rats following hypoxic brain injury. Furthermore, inhibition of Notch caused a remarkable decrease in NF-κB/p65 expression and translocation. Moreover, downregulation of either VEGF or NF-κB/p65 reduced astrocytic proliferation. Taken together, these results demonstrated that Notch-1 signaling was activated in hypoxic astrocytes and regulated astrocytic proliferation and activation by suppressing VEGF or NF-κB/p65 signaling pathway. Therefore, Notch signaling is a potential therapeutic strategy in hypoxia brain damage.
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, 250012 Jinan, China. Electronic address: ymzhang@sdu.edu.cn.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, 250012 Jinan, China.
authors.forename: Kun
authors.initials: K
authors.lastname: He
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, 250012 Jinan, China.
authors.forename: Fuwu
authors.initials: F
authors.lastname: Wang
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, 250012 Jinan, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Qilu Hospital of Shandong University, 250012 Jinan, Shandong, China. Electronic address: LDJ9741@163.com.
authors.forename: Dejie
authors.initials: D
authors.lastname: Liu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D061251:Primary Cell Culture; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D004151:Dipeptides; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D016328:NF-kappa B; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D053829:Amyloid Precursor Protein Secretases
keywords: Activation; Astrocytes; Hypoxia; Notch; Proliferation