title: Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2.
abstract: The bone morphogenic protein antagonist gremlin is expressed during embryonic development and under different pathologic conditions, including cancer. Gremlin is a proangiogenic protein belonging to the cystine-knot superfamily that includes transforming growth factor-β proteins and the angiogenic vascular endothelial growth factors (VEGFs). Here, we demonstrate that gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals, in a bone morphogenic protein-independent manner. Similar to VEGF-A, gremlin activates VEGFR2 in endothelial cells, leading to VEGFR2-dependent angiogenic responses in vitro and in vivo. Gremlin thus represents a novel proangiogenic VEGFR2 agonist distinct from the VEGF family ligands with implications in vascular development, angiogenesis-dependent diseases, and tumor neovascularization.
authors.affiliation: Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Viale Europa 11, Brescia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mitola
authors.forename: Cosetta
authors.initials: C
authors.lastname: Ravelli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Moroni
authors.forename: Valentina
authors.initials: V
authors.lastname: Salvi
authors.forename: Daria
authors.initials: D
authors.lastname: Leali
authors.forename: Kurt
authors.initials: K
authors.lastname: Ballmer-Hofer
authors.forename: Luca
authors.initials: L
authors.lastname: Zammataro
authors.forename: Marco
authors.initials: M
authors.lastname: Presta
mesh_terms: D000818:Animals; D002417:Cattle; D002460:Cell Line; D002645:Chickens; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000819:agonists* / Q000378:metabolism*
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2