Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
J Cell Sci. 2010 May 15;123(Pt 10):1684-92. doi: 10.1242/jcs.061556. Epub 2010 Apr 20.
Members of the bone morphogenetic protein (BMP) family have been implicated in the development and maintenance of vascular systems. Whereas members of the BMP-2/4 and osteogenic protein-1 groups signal via activin receptor-like kinase (ALK)-2, ALK-3 and ALK-6, BMP-9 and BMP-10 have been reported to bind to ALK-1 in endothelial cells. However, the roles of BMP-9-ALK-1 signaling in the regulation of endothelial cells have not yet been fully elucidated. Here, using various systems, we examined the effects of BMP-9 on the proliferation of endothelial cells. Vascular-tube formation from ex vivo allantoic explants of mouse embryos was promoted by BMP-9. BMP-9, as well as BMP-4 and BMP-6, also induced the proliferation of in-vitro-cultured mouse embryonic-stem-cell-derived endothelial cells (MESECs) by inducing the expression of vascular endothelial growth factor receptor 2 and Tie2, a receptor for angiopoietin-1. A decrease in ALK-1 expression or expression of constitutively active ALK-1 in MESECs abrogated and mimicked the effects of BMP-9 on the proliferation of MESECs, respectively, suggesting that BMP-9 promotes the proliferation of these cells via ALK-1. Furthermore, in vivo angiogenesis was promoted by BMP-9 in a Matrigel plug assay and in a BxPC3 xenograft model of human pancreatic cancer. Consistent with these in vivo findings, BMP-9 enhanced the proliferation of in-vitro-cultured normal endothelial cells from dermal tissues of adult mice and of tumor-associated endothelial cells isolated from tumor xenografts in host mice. These findings suggest that BMP-9 signaling activates the endothelium tested in the present study via ALK-1.
骨形态发生蛋白（BMP）家族的成员被认为参与了血管系统的发育和维持。BMP-2/4 和骨形成蛋白-1 组的成员通过激活素受体样激酶（ALK）-2、ALK-3 和 ALK-6 发出信号，而 BMP-9 和 BMP-10 则被报道在血管内皮细胞中与 ALK-1 结合。然而，BMP-9-ALK-1 信号在调节内皮细胞中的作用尚未完全阐明。在这里，我们使用各种系统研究了 BMP-9 对内皮细胞增殖的影响。BMP-9 促进了来自鼠胚的离体尿囊 explants 的血管管形成。BMP-9 以及 BMP-4 和 BMP-6，也通过诱导血管内皮生长因子受体 2 和血管生成素-1 的受体 Tie2 的表达，诱导体外培养的鼠胚胎干细胞衍生的内皮细胞（MESECs）的增殖。MESECs 中 ALK-1 表达的减少或组成性激活的 ALK-1 的表达分别消除和模拟了 BMP-9 对 MESECs 增殖的影响，表明 BMP-9 通过 ALK-1 促进这些细胞的增殖。此外，BMP-9 在 Matrigel 塞植入物和人胰腺癌细胞的 BxPC3 异种移植模型中促进了体内血管生成。与这些体内发现一致，BMP-9 增强了体外培养的来自成年小鼠皮肤组织的正常内皮细胞和从宿主小鼠肿瘤异种移植中分离的肿瘤相关内皮细胞的增殖。这些发现表明，BMP-9 信号通过 ALK-1 激活了本研究中测试的内皮细胞。
