title: BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo.
abstract: 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.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ohga
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Morishita
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hida
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Watabe
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000482:Allantois / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000196:embryology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D055427:Growth Differentiation Factor 2 / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D009368:Neoplasm Transplantation; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D055427:Growth Differentiation Factor 2; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II