title: Constitutive notch signaling in adult transgenic mice inhibits bFGF-induced angiogenesis and blocks ovarian follicle development.
abstract: Notch signaling is important in angiogenesis during embryonic development. However, the embryonic lethal phenotypes of knock-out and transgenic mice have precluded studies of the role of Notch post-natally. To develop a mouse model that would bypass the embryonic lethal phenotype and investigate the possible role of Notch signaling in adult vessel growth, we developed transgenic mice with Cre-conditional expression of the constitutively active intracellular domain of Notch1 (IC-Notch1). Double transgenic IC-Notch1/Tie2-Cre embryos with endothelial specific IC-Notch1 expression died at embryonic day 9.5. They displayed collapsed and leaky blood vessels and defects in angiogenesis development. A tetracycline-inducible system was used to express Cre recombinase postnatally in endothelial cells. In adult mice, IC-Notch1 expression inhibited bFGF-induced neovascularization and female mice lacked mature ovarian follicles, which may reflect the block in bFGF-induced angiogenesis required for follicle growth. Our results demonstrate that Notch signaling is important for both embryonic and adult angiogenesis and indicate that the Notch signaling pathway may be a useful target for angiogenic therapies.
authors.affiliation: Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, Toronto, Ontario, M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Laboratory of Microvascular Medicine, Medical Research Center, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Liu
authors.forename: Urban
authors.initials: U
authors.lastname: Deutsch
authors.forename: James
authors.initials: J
authors.lastname: Jeong
authors.forename: Corrinne G
authors.initials: CG
authors.lastname: Lobe
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000009:adverse effects*; D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D006080:Ovarian Follicle / Q000196:embryology* / Q000254:growth & development; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013752:Tetracycline / Q000494:pharmacology
chemical_list: D043925:Angiogenesis Inducing Agents; D051880:Receptors, Notch; D016222:Fibroblast Growth Factor 2; C045073:Cre recombinase; D019426:Integrases; D013752:Tetracycline
keywords: Notch signaling; angiogenesis; basic FGF; follicular development; transgenic mice