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Blood, 1 March 2007, Vol. 109, No. 5, pp. 1834-1840.
Prepublished online as a Blood First Edition Paper on October 31, 2006; DOI 10.1182/blood-2006-06-032276.
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CHEMOKINES, CYTOKINES, AND INTERLEUKINS
Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor
Helena Stabile1,
Stefania Mitola1,
Emanuela Moroni1,
Mirella Belleri1,
Stefania Nicoli1,
Daniela Coltrini2,
Francesco Peri3,
Antonello Pessi4,
Laura Orsatti4,
Fabio Talamo4,
Vincent Castronovo5,
David Waltregny6,
Franco Cotelli7,
Domenico Ribatti8, and
Marco Presta1
1 Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy;
2 Unit of Histology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy;
3 Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy;
4 Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Rome, Italy;
5 Metastasis Research Laboratory, Center of Experimental Cancer Research, University of Liège, Belgium;
6 Department of Pathology, Center of Experimental Cancer Research, University of Liège, Belgium;
7 Department of Biology, University of Milan, Italy;
8 Department of Human Anatomy and Histology, University of Bari, Italy
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.
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