Tmem2 Regulates Embryonic Vegf Signaling by Controlling Hyaluronic Acid Turnover

Jessica E De Angelis, Anne K Lagendijk, Huijun Chen, Alisha Tromp, Neil I Bower, Kathryn A Tunny, Andrew J Brooks, Jeroen Bakkers, Mathias Francois, Alpha S Yap, Cas Simons, Carol Wicking, Benjamin M Hogan, Kelly A Smith

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Angiogenesis is responsible for tissue vascularization during development, as well as in pathological contexts, including cancer and ischemia. Vascular endothelial growth factors (VEGFs) regulate angiogenesis by acting through VEGF receptors to induce endothelial cell signaling. VEGF is processed in the extracellular matrix (ECM), but the complexity of ECM control of VEGF signaling and angiogenesis remains far from understood. In a forward genetic screen, we identified angiogenesis defects in tmem2 zebrafish mutants that lack both arterial and venous Vegf/Vegfr/Erk signaling. Strikingly, tmem2 mutants display increased hyaluronic acid (HA) surrounding developing vessels. Angiogenesis in tmem2 mutants was rescued, or restored after failed sprouting, by degrading this increased HA. Furthermore, oligomerized HA or overexpression of Vegfc rescued angiogenesis in tmem2 mutants. Based on these data, and the known structure of Tmem2, we find that Tmem2 regulates HA turnover to promote normal Vegf signaling during developmental angiogenesis.

Original languageEnglish
Pages (from-to)123-136
Number of pages14
JournalDevelopmental Cell
Volume40
Issue number2
DOIs
Publication statusPublished - 23 Jan 2017

Keywords

  • Animals
  • Arteries
  • Embryo, Nonmammalian
  • Endothelial Cells
  • Hyaluronic Acid
  • Membrane Proteins
  • Mutation
  • Neovascularization, Physiologic
  • Phenotype
  • Polymerization
  • Signal Transduction
  • Torso
  • Vascular Endothelial Growth Factor A
  • Veins
  • Zebrafish
  • Zebrafish Proteins
  • Journal Article
  • Research Support, Non-U.S. Gov't

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