title: Man1, an inner nuclear membrane protein, regulates vascular remodeling by modulating transforming growth factor beta signaling.
abstract: A growing number of integral inner nuclear membrane (INM) proteins have been implicated in diverse cellular functions. Man1, an INM protein, has recently been shown to regulate transforming growth factor (Tgf) beta superfamily signaling by interacting with receptor-associated Smads. However, the in vivo roles of Man1 have not been fully characterized. Here, we show that Man1 regulates vascular remodeling by analyzing Man1-deficient embryos lacking the Smad interacting domain. Man1-deficient embryos die at midgestation because of defects in embryonic vasculature; the primary capillary plexus forms, but subsequent remodeling is perturbed. It has been proposed that the angiogenesis process is divided into two balanced phases, the activation and resolution/maturation phases, both of which are regulated by Tgfbeta1. We have demonstrated, in Man1-deficient embryos, the expression of Tgfb1 is upregulated and Smad2/3 signaling is abnormally activated, resulting in increased extracellular matrix deposition, a hallmark of the resolution phase of angiogenesis. We have also showed that the recruitment of mural cells to the vascular wall is severely disturbed in mutants, which may lead to disruption of intercellular communication between endothelial and mural cells required for proper vascular remodeling. These results have revealed a novel role for Man1 in angiogenesis and provide the first evidence that vascular remodeling can be regulated at the INM through the interaction between Man1 and Smads.
authors.affiliation: The 21st Century Center of Excellence Program, Akita University School of Medicine, Hondo 1-1-1, Akita, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ishimura
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Ng
authors.forename: Masanori
authors.initials: M
authors.lastname: Taira
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Osada
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities / Q000196:embryology*; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D002470:Cell Survival; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000098:blood supply* / Q000166:cytology; D004625:Embryo, Nonmammalian; D005804:Genes, Lethal; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D018919:Neovascularization, Physiologic / Q000235:genetics*; D055457:Nodal Protein; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017384:Sequence Deletion; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014981:Xenopus; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C485769:LEMD3 protein, Xenopus; C515012:Man1 protein, mouse; D008565:Membrane Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; D009687:Nuclear Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D029867:Xenopus Proteins; D028341:Activins