TY - JOUR
T1 - Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor
AU - Stabile, Helena
AU - Mitola, Stefania
AU - Moroni, Emanuela
AU - Belleri, Mirella
AU - Nicoli, Stefania
AU - Coltrini, Daniela
AU - Peri, Francesco
AU - Pessi, Antonello
AU - Orsatti, Laura
AU - Talamo, Fabio
AU - Castronovo, Vincent
AU - Waltregny, David
AU - Cotelli, Franco
AU - Ribatti, Domenico
AU - Presta, Marco
PY - 2007/3/1
Y1 - 2007/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33847402760&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847402760&partnerID=8YFLogxK
U2 - 10.1182/blood-2006-06-032276
DO - 10.1182/blood-2006-06-032276
M3 - Article
C2 - 17077323
AN - SCOPUS:33847402760
VL - 109
SP - 1834
EP - 1840
JO - Blood
JF - Blood
SN - 0006-4971
IS - 5
ER -