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-β (TGF-β) 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.

Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome

“…In addition, endoglin has been shown to interact with zyxin-related protein 1 resulting in a dramatic change in the structure of the actin cytoskeleton and the localization of zyxinrelated protein 1 (Sanz-Rodriguez et al, 2004). Second, in addition to TGF-b1, endoglin can bind, in association with different TGF-b superfamily receptors, to BMP2, BMP7, BMP9, activin A and TGF-b3 (Cheifetz et al, 1992;Barbara et al, 1999;Scharpfenecker et al, 2007), and has been reported to have a functional role in modulating responses to BMP2 (Ishibashi et al, 2010) and BMP7 (Scherner et al, 2007) in periodontal ligament cells and myoblasts, respectively. Although there are no published reports of endoglin modulating the response to other TGF-b family ligands in epithelial cells, it will be of interest in the future to determine whether the TGF-b1-independent functions of endoglin expressed on tumor cells may be mediated by binding to alternate ligands and/ or other TGF-b superfamily receptors.…”

Osteoinductive signals and heterotopic ossification

“…While BMP-9-induced heterotopic ossification was shown to be mediated through the ALK1 type 1 receptor, the study does not address whether ALK1 acts independently of other BMP type 1 receptors or other receptors contribute to heterotopic ossification, perhaps through type 1 BMP receptor heterodimer formation with ALK1. Although experimental data support that ALK1 binds BMP-9 and activates the BMP-Smad1/5/ 8 pathway in response to BMP-9, (11) there is additional evidence that BMP-9 binds to and signals through receptors other than ALK1, including ALK2, (12,13) the BMP type 1 receptor that is mutated in patients with FOP. (4) It is interesting to speculate that in these experiments, BMP-9 in the context of injury is inducing heterotopic ossification by activating ALK1-ALK2 heterodimers or that a sequential series of BMP signaling events mediated independently by ALK1 and ALK2 is required for induction of heterotopic ossification.…”

Maladie de Rendu-Osler

“…Ce modèle est actuellement remis en cause car en 2006, notre groupe a identifié les facteurs BMP9 et BMP10 comme des ligands spécifiques et de forte affinité d'ALK1 [24]. Ces résultats ont été confirmés depuis par un autre groupe [25]. L'expression de BMP10 semble restreinte au stade embryonnaire et jouerait un rôle dans le développement du coeur.…”

“…Le rôle du récepteur ALK1, en l'absence de ligand spécifique, a longtemps été débattu dans la littérature [27,28]. L'identification de son ligand BMP9 a permis de confirmer clairement son rôle dans l'inhibition de la prolifération, de la migration et du bourgeonnement des cellules endothéliales in vitro ainsi que de la néo-angiogenèse in vivo [24][25][26]. Ces données indiquent que BMP9 serait un facteur-clé de la phase de maturation de l'angiogenèse ( Figure 1) et sa présence dans le sang suggère son rôle dans le maintien de la quiescence vasculaire chez l'adulte [26].…”