title: Notch-1 signalling is activated in brain arteriovenous malformations in humans.
abstract: A role for the Notch signalling pathway in the formation of arteriovenous malformations during development has been suggested. However, whether Notch signalling is involved in brain arteriovenous malformations in humans remains unclear. Here, we performed immunohistochemistry on surgically resected brain arteriovenous malformations and found that, compared with control brain vascular tissue, Notch-1 signalling was activated in smooth muscle and endothelial cells of the lesional tissue. Western blotting showed an activated form of Notch-1 in brain arteriovenous malformations, irrespective of clinical presentation and with or without preoperative embolization, but not in normal cerebral vessels from controls. In addition, the Notch-1 ligands Jagged-1 and Delta-like-4 and the downstream Notch-1 target Hes-1 were increased in abundance and activated in human brain arteriovenous malformations. Finally, increased angiogenesis was found in adult rats treated with a Notch-1 activator. Our findings suggest that activation of Notch-1 signalling is a phenotypic feature of brain arteriovenous malformations, and that activation of Notch-1 in normal vasculature induces a pro-angiogenic state, which may contribute to the development of vascular malformations.
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical College, Wenzhou, China.
authors.forename: Qichuan
authors.initials: Q
authors.lastname: ZhuGe
authors.forename: Ming
authors.initials: M
authors.lastname: Zhong
authors.forename: WeiMing
authors.initials: W
authors.lastname: Zheng
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Yang
authors.forename: XiaoOu
authors.initials: X
authors.lastname: Mao
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Gourong
authors.initials: G
authors.lastname: Chen
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Chen
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lawton
authors.forename: William L
authors.initials: WL
authors.lastname: Young
authors.forename: David A
authors.initials: DA
authors.lastname: Greenberg
authors.forename: Kunlin
authors.initials: K
authors.lastname: Jin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002536:Cerebral Arteries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002550:Cerebral Veins / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002648:Child; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D002538:Intracranial Arteriovenous Malformations / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D051881:Receptor, Notch1 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000072056:Transcription Factor HES-1; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; C424126:DLL4 protein, human; C489735:Hes1 protein, rat; C000606273:JAG1 protein, human; C000606275:Jag1 protein, rat; C497761:NOTCH1 protein, human