BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo
BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo
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DOI：
10.1242/jcs.061556
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发表时间：
2010-05-15
影响因子：
4
通讯作者：
Watabe, Tetsuro
中科院分区：
文献类型：
--
作者：
Suzuki, Yuka;Ohga, Noritaka;Watabe, Tetsuro
骨形态发生蛋白（BMP）家族成员与血管系统的发育和维持有关。尽管BMP-2/4和成骨蛋白-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，但据报道BMP-9和BMP-10在内皮细胞中与ALK-1结合。然而，BMP-9-ALK-1信号在内皮细胞调节中的作用尚未完全阐明。在这里，使用各种系统，我们研究了BMP-9对内皮细胞增殖的影响。BMP-9促进小鼠胚胎离体尿囊外植体血管管形成。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Tie 2（血管生成素-1的受体）的表达来诱导体外培养的小鼠胚胎干细胞衍生的内皮细胞（MESEC）的增殖。MESEC中ALK-1表达或组成型活性ALK-1表达的降低分别消除和模拟BMP-9对MESEC增殖的作用，表明BMP-9通过ALK-1促进这些细胞的增殖。此外，在基质胶塞测定和人胰腺癌的BxPC 3异种移植模型中，BMP-9促进体内血管生成。与这些体内发现一致，BMP-9增强了体外培养的成年小鼠真皮组织正常内皮细胞和从宿主小鼠肿瘤异种移植物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激活本研究中测试的内皮。
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.