title: Neuronal sFlt1 and Vegfaa determine venous sprouting and spinal cord vascularization.
abstract: Formation of organ-specific vasculatures requires cross-talk between developing tissue and specialized endothelial cells. Here we show how developing zebrafish spinal cord neurons coordinate vessel growth through balancing of neuron-derived Vegfaa, with neuronal sFlt1 restricting Vegfaa-Kdrl mediated angiogenesis at the neurovascular interface. Neuron-specific loss of flt1 or increased neuronal vegfaa expression promotes angiogenesis and peri-neural tube vascular network formation. Combining loss of neuronal flt1 with gain of vegfaa promotes sprout invasion into the neural tube. On loss of neuronal flt1, ectopic sprouts emanate from veins involving special angiogenic cell behaviours including nuclear positioning and a molecular signature distinct from primary arterial or secondary venous sprouting. Manipulation of arteriovenous identity or Notch signalling established that ectopic sprouting in flt1 mutants requires venous endothelium. Conceptually, our data suggest that spinal cord vascularization proceeds from veins involving two-tiered regulation of neuronal sFlt1 and Vegfaa via a novel sprouting mode.
authors.affiliation: Department of Cell and Developmental Biology, Institute of Zoology (ZOO) Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 4, 76131 Karlsruhe, Germany.|Institute for Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Wild
authors.affiliation: Department of Cell and Developmental Biology, Institute of Zoology (ZOO) Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 4, 76131 Karlsruhe, Germany.|Institute for Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Klems
authors.affiliation: Institute for Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Masanari
authors.initials: M
authors.lastname: Takamiya
authors.affiliation: Institute for Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.|Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, 8000 Aarhus C, Denmark.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Institute for Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Strähle
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Research Institute, 5-7-1 Fujisirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Research Institute, 5-7-1 Fujisirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.affiliation: Institute for Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, University of Münster, Mendelstr. 7, 48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence, (EXC 1003-CiM), University of Münster, Waldeyerstraße 15, 48149 Münster, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: van Impel
authors.affiliation: Institute for Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, University of Münster, Mendelstr. 7, 48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence, (EXC 1003-CiM), University of Münster, Waldeyerstraße 15, 48149 Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte-Merker
authors.affiliation: Department of Translational Oncology, Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Ave., M4N 3M5 Toronto, Canada.
authors.forename: Janna
authors.initials: J
authors.lastname: Krueger
authors.affiliation: Department of Cell and Developmental Biology, Institute of Zoology (ZOO) Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 4, 76131 Karlsruhe, Germany.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Preau
authors.affiliation: Department of Cell and Developmental Biology, Institute of Zoology (ZOO) Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 4, 76131 Karlsruhe, Germany.|Institute for Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: le Noble
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000166:cytology; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D009154:Mutation; D018919:Neovascularization, Physiologic; D009474:Neurons / Q000502:physiology*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000098:blood supply / Q000196:embryology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D014680:Veins / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C583604:Vegfaa protein, zebrafish; D029961:Zebrafish Proteins; C583603:FLT1 protein, zebrafish; D040281:Vascular Endothelial Growth Factor Receptor-1