BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis
ABSTRACT Genetic studies in mice and humans have shown that the transforming growth factor-beta (TGF-beta) type-I receptor activin receptor-like kinase 1 (ALK1) and its co-receptor endoglin play an important role in vascular development and angiogenesis. Here, we demonstrate that ALK1 is a signalling receptor for bone morphogenetic protein-9 (BMP-9) in endothelial cells (ECs). BMP-9 bound with high affinity to ALK1 and endoglin, and weakly to the type-I receptor ALK2 and to the BMP type-II receptor (BMPR-II) and activin type-II receptor (ActR-II) in transfected COS cells. Binding of BMP-9 to ALK2 was greatly facilitated when BMPR-II or ActR-II were co-expressed. Whereas BMP-9 predominantly bound to ALK1 and BMPR-II in ECs, it bound to ALK2 and BMPR-II in myoblasts. In addition, we observed binding of BMP-9 to ALK1 and endoglin in glioblastoma cells. BMP-9 activated Smad1 and/or Smad5, and induced ID1 protein and endoglin mRNA expression in ECs. Furthermore, BMP-9 was found to inhibit basic fibroblast growth factor (bFGF)-stimulated proliferation and migration of bovine aortic ECs (BAECs) and to block vascular endothelial growth factor (VEGF)-induced angiogenesis. Taken together, these results suggest that BMP-9 is a physiological ALK1 ligand that plays an important role in the regulation of angiogenesis.
- SourceAvailable from: Ling Yu
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- "BMP9 is a systemically available factor that functions in regulating vascular structure postnatally (Chen et al., 2013; Ricard et al., 2012), and has been shown to be either proangiogenic and anti-angiogenic in different assays (David et al., 2008; Scharpfenecker et al., 2007; Suzuki et al., 2010). While Bmp9 transcripts are not detected during digit regeneration, treating amputated digits with BMP9 (500 ng/µl) resulted in the complete inhibition of regeneration (Figure 2A). "
ABSTRACT: The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti-angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J., Muneoka, K., 2010. BMP signaling induces digit regeneration in neonatal mice. Development. 137, 551–9). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with VEGF enhances angiogenesis but inhibits regeneration. We next tested BMP9, another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure was mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with PEDF. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration.This article is protected by copyright. All rights reserved.06/2014; 1(3). DOI:10.1002/reg2.24
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- "BMP binding to the heterodimeric complex of BMPR type 1 and type 2 facilitates cross-phosphorylation of the type I receptor by the constitutively active type II receptor, leading to downstream signaling . While ALK1, ALK5 and endoglin have been described as potential BMP9 type I receptors, recent studies have further investigated the receptors necessary for BMP9-mediated osteogenesis    . Luo et al. performed a comprehensive analysis of seven functional type I receptors in BMP9- mediated osteogenic differentiation of MSCs . "
ABSTRACT: Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily and play a critical role in skeletal development, bone formation and stem cell differentiation. Disruptions in BMP signaling result in a variety of skeletal and extraskeletal anomalies. BMP9 is a poorly characterized member of the BMP family and is among the most osteogenic BMPs, promoting osteoblastic differentiation of mesenchymal stem cells (MSCs) both in vitro and in vivo. Recent findings from various in vivo and molecular studies strongly suggest that the mechanisms governing BMP9-mediated osteoinduction differ from other osteogenic BMPs. Many signaling pathways with diverse functions have been found to play a role in BMP9-mediated osteogenesis. Several of these pathways are also critical in the differentiation of other cell lineages, including adipocytes and chondrocytes. While BMP9 is known to be a potent osteogenic factor, it also influences several other pathways including cancer development, angiogenesis and myogenesis. Although BMP9 has been demonstrated as one of the most osteogenic BMPs, relatively little is known about the specific mechanisms responsible for these effects. BMP9 has demonstrated efficacy in promoting spinal fusion and bony non-union repair in animal models, demonstrating great translational promise. This review aims to summarize our current knowledge of BMP9-mediated osteogenesis by presenting recently completed work which may help us to further elucidate these pathways.01/2013; 2(1):1-21.
Tumor Angiogenesis, 02/2012; , ISBN: 978-953-51-0009-6
- "In primary Human Dermal Microvascular Endothelial Cells (HMVEC-D), obtained from the skin, an organ whose vasculature is clearly affected in HHT patients, activation of ALK1 or stimulation with BMP9 inhibited cell proliferation and migration, while increasing SMAD1- 5 target gene expression (David et al., 2007; Lamouille et al., 2002). Over-expression of ALK1 also decreased proliferation of primary HUVEC cells (Ota et al., 2002) and BMP9 blocked the proliferative effect of basic FGF (bFGF) on primary endothelial cells (Scharpfenecker et al., 2007). Based on these in vitro results, and on the fact that BMP9 inhibited vessel formation in a bFGF-driven in vivo angiogenesis assay (David et al., 2008), BMP9/ALK1 signaling was proposed to function in the resolution phase of angiogenesis, during which endothelial cell proliferation and migration shut down and vessel maturation and differentiation proceeds. "