Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor.
Angiogenesis plays a key role in various physiologic and pathologic conditions, including tumor growth. Drm/gremlin, a member the Dan family of bone morphogenic protein (BMP) antagonists, is commonly thought to affect different processes during growth, differentiation, and development by heterodimerizing various BMPs. Here, we identify Drm/gremlin as a novel proangiogenic factor expressed by endothelium. Indeed, Drm/gremlin was purified to homogeneity from the conditioned medium of transformed endothelial cells using an endothelial-cell sprouting assay to follow protein isolation. Accordingly, recombinant Drm/gremlin stimulates endothelial-cell migration and invasion in fibrin and collagen gels, binds with high affinity to various endothelial cell types, and triggers tyrosine phosphorylation of intracellular signaling proteins. Also, Drm/gremlin induces neovascularization in the chick embryo chorioallantoic membrane. BMP4 does not affect Drm/gremlin interaction with endothelium, and both molecules exert a proangiogenic activity in vitro and in vivo when administered alone or in combination. Finally, Drm/gremlin is produced by the stroma of human tumor xenografts in nude mice, and it is highly expressed in endothelial cells of human lung tumor vasculature when compared with non-neoplastic lung. Our observations point to a novel, previously unrecognized capacity of Drm/gremlin to interact directly with target endothelial cells and to modulate angiogenesis.
Stabile
Helena
H
Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy.
Mitola
Stefania
S
Moroni
Emanuela
E
Belleri
Mirella
M
Nicoli
Stefania
S
Coltrini
Daniela
D
Peri
Francesco
F
Pessi
Antonello
A
Orsatti
Laura
L
Talamo
Fabio
F
Castronovo
Vincent
V
Waltregny
David
D
Cotelli
Franco
F
Ribatti
Domenico
D
Presta
Marco
M
D000595:Amino Acid Sequence; D043925:Angiogenesis Inducing Agents / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D016207:Cytokines; D042783:Endothelial Cells / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D043925:Angiogenesis Inducing Agents; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; C113178:Grem1 protein, mouse