Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2.
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.
Mitola
Stefania
S
Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Viale Europa 11, Brescia, Italy.
Ravelli
Cosetta
C
Moroni
Emanuela
E
Salvi
Valentina
V
Leali
Daria
D
Ballmer-Hofer
Kurt
K
Zammataro
Luca
L
Presta
Marco
M
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*
C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2