title: Opposing effects of circadian clock genes bmal1 and period2 in regulation of VEGF-dependent angiogenesis in developing zebrafish.
abstract: Molecular mechanisms underlying circadian-regulated physiological processes remain largely unknown. Here, we show that disruption of the circadian clock by both constant exposure to light and genetic manipulation of key genes in zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. Using a promoter-reporter system consisting of various deleted vegf-promoter mutants, we show that Bmal1 directly binds to and activates the vegf promoter via E-boxes. Additionally, we provide evidence that knockdown of Bmal1 leads to impaired Notch-inhibition-induced vascular sprouting. These results shed mechanistic insight on the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Lasse Dahl
authors.initials: LD
authors.lastname: Jensen
authors.forename: Ziquan
authors.initials: Z
authors.lastname: Cao
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Yang
authors.forename: Lars
authors.initials: L
authors.lastname: Bräutigam
authors.forename: Patrik
authors.initials: P
authors.lastname: Andersson
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Eric
authors.initials: E
authors.lastname: Wahlberg
authors.forename: Toste
authors.initials: T
authors.lastname: Länne
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hosaka
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified / Q000196:embryology / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000502:physiology*; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D056930:ARNTL Transcription Factors; D056950:Period Circadian Proteins; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins