title: Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor.
abstract: 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.
authors.affiliation: Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy.
authors.forename: Helena
authors.initials: H
authors.lastname: Stabile
authors.forename: Stefania
authors.initials: S
authors.lastname: Mitola
authors.forename: Emanuela
authors.initials: E
authors.lastname: Moroni
authors.forename: Mirella
authors.initials: M
authors.lastname: Belleri
authors.forename: Stefania
authors.initials: S
authors.lastname: Nicoli
authors.forename: Daniela
authors.initials: D
authors.lastname: Coltrini
authors.forename: Francesco
authors.initials: F
authors.lastname: Peri
authors.forename: Antonello
authors.initials: A
authors.lastname: Pessi
authors.forename: Laura
authors.initials: L
authors.lastname: Orsatti
authors.forename: Fabio
authors.initials: F
authors.lastname: Talamo
authors.forename: Vincent
authors.initials: V
authors.lastname: Castronovo
authors.forename: David
authors.initials: D
authors.lastname: Waltregny
authors.forename: Franco
authors.initials: F
authors.lastname: Cotelli
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Marco
authors.initials: M
authors.lastname: Presta
mesh_terms: 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
chemical_list: D043925:Angiogenesis Inducing Agents; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; C113178:Grem1 protein, mouse