Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor
Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor
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DOI：
10.1182/blood-2006-06-032276
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发表时间：
2007-03-01
期刊：
影响因子：
20.3
通讯作者：
Presta, Marco
中科院分区：
文献类型：
--
作者：
Stabile, Helena;Mitola, Stefania;Presta, Marco
血管生成在包括肿瘤生长在内的各种生理和病理条件中起关键作用。Drm/gremlin是骨形态发生蛋白（BMP）拮抗剂Dan家族的成员，通常被认为通过异源二聚化各种BMP来影响生长、分化和发育期间的不同过程。在这里，我们确定Drm/gremlin作为一种新的促血管生成因子表达的内皮细胞。事实上，Drm/gremlin从转化的内皮细胞的条件培养基中纯化至均一，使用内皮细胞发芽测定法进行蛋白质分离。因此，重组Drm/gremlin刺激纤维蛋白和胶原凝胶中的内皮细胞迁移和侵入，以高亲和力结合各种内皮细胞类型，并触发细胞内信号蛋白的酪氨酸磷酸化。此外，Drm/gremlin诱导鸡胚绒毛尿囊膜中的新血管形成。BMP 4不影响Drm/gremlin与内皮的相互作用，并且当单独或组合施用时，两种分子在体外和体内发挥促血管生成活性。最后，Drm/gremlin由裸鼠中的人肿瘤异种移植物的基质产生，并且当与非肿瘤性肺相比时，其在人肺肿瘤血管系统的内皮细胞中高度表达。我们的观察指出，一种新的，以前未被认识的能力Drm/gremlin直接与靶内皮细胞相互作用，并调节血管生成。
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.