The bone morphogenic protein antagonist Drm/gremlin is a novel pro- angiogenic factor

Angiogenesis plays a key role in various physiological and pathological 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 pro-angiogenic 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 pro-angiogenic 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 to 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.