Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor

Helena Stabile, Stefania Mitola, Emanuela Moroni, Mirella Belleri, Stefania Nicoli, Daniela Coltrini, Francesco Peri, Antonello Pessi, Laura Orsatti, Fabio Talamo, Vincent Castronovo, David Waltregny, Franco Cotelli, Domenico Ribatti, Marco Presta

Research output: Contribution to journalArticlepeer-review

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 nonneoplastic lung. Our observations point to a novel, previously unrecognized capacity of Drm/gremlin to interact directly with target endothelial cells and to modulate angiogenesis.

Original languageEnglish
Pages (from-to)1834-1840
Number of pages7
JournalBlood
Volume109
Issue number5
DOIs
Publication statusPublished - Mar 1 2007

ASJC Scopus subject areas

  • Hematology

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