Tmem2 Regulates Embryonic Vegf Signaling by Controlling Hyaluronic Acid Turnover

TY - JOUR

T1 - Tmem2 Regulates Embryonic Vegf Signaling by Controlling Hyaluronic Acid Turnover

AU - De Angelis, Jessica E

AU - Lagendijk, Anne K

AU - Chen, Huijun

AU - Tromp, Alisha

AU - Bower, Neil I

AU - Tunny, Kathryn A

AU - Brooks, Andrew J

AU - Bakkers, Jeroen

AU - Francois, Mathias

AU - Yap, Alpha S

AU - Simons, Cas

AU - Wicking, Carol

AU - Hogan, Benjamin M

AU - Smith, Kelly A

N1 - Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

PY - 2017/1/23

Y1 - 2017/1/23

N2 - 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.

AB - 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.

KW - Animals

KW - Arteries

KW - Embryo, Nonmammalian

KW - Endothelial Cells

KW - Hyaluronic Acid

KW - Membrane Proteins

KW - Mutation

KW - Neovascularization, Physiologic

KW - Phenotype

KW - Polymerization

KW - Signal Transduction

KW - Torso

KW - Vascular Endothelial Growth Factor A

KW - Veins

KW - Zebrafish

KW - Zebrafish Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.devcel.2016.12.017

DO - 10.1016/j.devcel.2016.12.017

M3 - Article

C2 - 28118600

SN - 1534-5807

VL - 40

SP - 123

EP - 136

JO - Developmental Cell

JF - Developmental Cell

IS - 2

ER -