title: Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth.
abstract: Endoglin (CD105), a transmembrane protein of the transforming growth factor β superfamily, plays a crucial role in angiogenesis. Mutations in endoglin result in the vascular defect known as hereditary hemorrhagic telangiectasia (HHT1). The soluble form of endoglin was suggested to contribute to the pathogenesis of preeclampsia. To obtain further insight into its function, we cloned, expressed, purified, and characterized the extracellular domain (ECD) of mouse and human endoglin fused to an immunoglobulin Fc domain. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays. We performed a function mapping analysis of the different domains of endoglin by examining their contributions to the selectivity and biological activity of the protein. The BMP9/BMP10 binding site was localized to the orphan domain of human endoglin composed of the amino acid sequence 26-359. We established that endoglin and type II receptors bind to overlapping sites on BMP9. In the in vivo chick chorioallantoic membrane assay, the mouse and the truncated human endoglin ECD-Fc both significantly reduced VEGF-induced vessel formation. Finally, murine endoglin ECD-Fc acted as an anti-angiogenic factor that decreased blood vessel sprouting in VEGF/FGF-induced angiogenesis in in vivo angioreactors and reduced the tumor burden in the colon-26 mouse tumor model. Together our findings indicate an important role of soluble endoglin ECD in the regulation of angiogenesis and highlight efficacy of endoglin-Fc as a potential anti-angiogenesis therapeutic agent.
authors: Acceleron Pharma, Cambridge, Massachusetts 02139, USA.
authors: Roselyne
authors: R
authors: Castonguay
authors: Eric D
authors: ED
authors: Werner
authors: Robert G
authors: RG
authors: Matthews
authors: Eleonora
authors: E
authors: Presman
authors: Aaron W
authors: AW
authors: Mulivor
authors: Nicolas
authors: N
authors: Solban
authors: Dianne
authors: D
authors: Sako
authors: R Scott
authors: RS
authors: Pearsall
authors: Kathryn W
authors: KW
authors: Underwood
authors: Jasbir
authors: J
authors: Seehra
authors: Ravindra
authors: R
authors: Kumar
authors: Asya V
authors: AV
authors: Grinberg
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D000071063:Endoglin; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000378:metabolism*; D055412:Growth Differentiation Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; C541386:BMP10 protein, human; C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; C064206:ENG protein, human; D000071063:Endoglin; C502004:Eng protein, mouse; C525887:GDF2 protein, human; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D052006:Bone Morphogenetic Protein Receptors, Type II