BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo

• Published in: Journal of cell science Vol. 123; no. 10; pp. 1684 - 1692
• Main Authors: Suzuki, Yuka, Ohga, Noritaka, Morishita, Yasuyuki, Hida, Kyoko, Miyazono, Kohei, Watabe, Tetsuro
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Limited 15.05.2010
• Subjects: Activin Receptors, Type II - metabolism; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Allantois - metabolism; Animals; Blood Vessels - drug effects; Blood Vessels - embryology; Cell Line, Tumor; Cell Proliferation - drug effects; Embryo, Mammalian; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Gene Expression Regulation, Developmental; Growth Differentiation Factor 2 - pharmacology; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Neoplasm Transplantation; Neovascularization, Physiologic - drug effects; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Signal Transduction - drug effects
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.061556

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.