title: Tmem2 Regulates Embryonic Vegf Signaling by Controlling Hyaluronic Acid Turnover.
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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: De Angelis
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Lagendijk
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Huijun
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Alisha
authors.initials: A
authors.lastname: Tromp
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Neil I
authors.initials: NI
authors.lastname: Bower
authors.affiliation: Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Tunny
authors.affiliation: Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brooks
authors.affiliation: Department of Cardiac Development and Genetics, Hubrecht Institute, University Medical Centre Utrecht, Utrecht 3584 CT, the Netherlands; Department of Medical Physiology, University Medical Centre Utrecht, Utrecht 3584 EA, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bakkers
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Mathias
authors.initials: M
authors.lastname: Francois
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Alpha S
authors.initials: AS
authors.lastname: Yap
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Cas
authors.initials: C
authors.lastname: Simons
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Carol
authors.initials: C
authors.lastname: Wicking
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: b.hogan@imb.uq.edu.au.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Hogan
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: k.smith@imb.uq.edu.au.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Smith
mesh_terms: D000818:Animals; D001158:Arteries / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D018919:Neovascularization, Physiologic; D010641:Phenotype; D058105:Polymerization; D015398:Signal Transduction; D060726:Torso / Q000098:blood supply; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014680:Veins / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; C568068:cemip2 protein, zebrafish; D006820:Hyaluronic Acid
keywords: VEGF; angiogenesis; extracellular matrix; hyaluronic acid; tmem2; zebrafish