Neuronal sFlt1 and Vegfaa determine venous sprouting and spinal cord vascularization

• Published in: Nature communications 2017-01, Vol.8 (1), p.13991-17, Article 13991
• Main Authors: Wild, Raphael, Klems, Alina, Takamiya, Masanari, Hayashi, Yuya, Strähle, Uwe, Ando, Koji, Mochizuki, Naoki, van Impel, Andreas, Schulte-Merker, Stefan, Krueger, Janna, Preau, Laetitia, le Noble, Ferdinand
• Format: Article
• Language: English
• Subjects: 14; 14/19; 14/35; 38; 38/39; 38/91; 42; 42/70; 631/136/16; 631/378/2632/1823; 64; 96; 96/31; Angiogenesis; Animals; Animals, Genetically Modified; Biology; Biomarkers - metabolism; Blood vessels; Coronary vessels; Embryo, Nonmammalian - cytology; Embryos; Endothelial Cells - metabolism; Endothelial Cells - physiology; Gene Expression Regulation, Developmental; Humanities and Social Sciences; multidisciplinary; Mutation; Neovascularization, Physiologic; Nervous system; Neurons; Neurons - physiology; Physiology; Proteins; Receptors, Notch - genetics; Receptors, Notch - metabolism; Science; Science (multidisciplinary); Spinal cord; Spinal Cord - blood supply; Spinal Cord - embryology; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Veins & arteries; Veins - embryology; Veins - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13991

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. The generation of vasculature in organs is regulated by cross-talk between the developing tissue and specialized endothelial cells. Here, the authors show that vessel growth feeding the zebrafish spinal cord is coordinated by balancing neuron-derived pro-angiogenic ligand Vegfaa and its receptor, sFlt1.