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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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Submitted June 28, 2006
Accepted October 16, 2006
The bone morphogenic protein antagonist Drm/gremlin is a novel pro-angiogenic 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, and Marco Presta*
Unit of General Pathology & Immunology, Dept of Biomedical Sciences & Biotechnology, University of Brescia, Italy
Unit of Histology, Dept of Biomedical Sciences & Biotechnology, University of Brescia, Italy
Dept of Biotechnology & Biosciences, University of Milano-Bicocca, Italy
Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Rome, Italy
Metastasis Research Laboratory, Center of Experimental Cancer Research, University of Liege, Belgium
Dept of Pathology, Center of Experimental Cancer Research, University of Liege, Belgium
Dept of Biology, University of Milano, Italy
Dept of Human Anatomy & Histology, University of Bari, Italy
* Corresponding author; email: presta{at}med.unibs.it.
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.
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