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BMP9, BMP10, and ALK1: An Emerging Vascular Signaling Pathway with Therapeutic Applications

Abstract

Bone morphogenetic proteins (BMPs) are growth factors of the TGFß family. Among them, BMP9 and BMP10 have been shown to bind with high affinity to a receptor expressed only on blood and lymphatic endothelial cells, ALK1 (activin receptor-like kinase 1), suggesting an important role for BMP9, BMP10, and ALK1 in vascular development. Indeed, mutations of ALK1 have been linked to two vascular diseases, the Rendu-Osler-Weber syndrome, also known as hemorrhagic hereditary telangiectasia, and pulmonary arterial hypertension. BMP9 is expressed by the liver, while BMP10 is mainly expressed by the heart and both are present in blood. The current working model is that BMP9 and BMP10 via ALK1 maintain a quiescent endothelial state. BMP9 and BMP10 have been recently shown to play a critical role in blood vessel development in an interchangeable manner. On the other hand, preliminary works seem to indicate that BMP9 plays a specific role in lymphatic development. Although the cellular functions of ALK1 are not completely understood, therapeutic treatment blocking ALK1 have already been developed. Two different approaches are ongoing: one, using the extracellular domain of ALK1 (ALK1ECD) that will trap any ligand able to bind to this soluble form of ALK1 and, the second, using a blocking anti-ALK1 antibody. Preliminary data from phase 1 clinical trials indicate no major toxicity with these two compounds and phase 2 clinical trials have started in patients suffering from different cancers. Taken together, these results clearly demonstrate that the BMP9/BMP10/ALK1 is an emerging vascular signaling pathway with potential therapeutic applications.

Keywords

  • Pulmonary Arterial Hypertension
  • Vascular Development
  • Hemorrhagic Hereditary Telangiectasia
  • Lymphatic Endothelial Cell
  • Hemorrhagic Hereditary Telangiectasia Patient

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Fig. 5.1

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Acknowledgments

I would like to thank Dr Emmnuelle Tillet, Dr Daniel Vittet, and Dr Jean-Jacques Feige for helpful discussions.

This work was supported by Inserm (U1036), CEA (iRTSV/BCI and LETI/DTBS), UJF, Association pour la Recherche sur le Cancer (postdoctoral grant to G.M. and grant N° SFI20111203720), the Groupement d’Entreprises Françaises de Lutte contre le Cancer (GEFLUC) Dauphiné-Savoie, the Comité Départemental de la Loire et de l’Isère de la Ligue contre le cancer, and AMRO (Association Malades du Rendu-Osler).

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Bailly, S. (2014). BMP9, BMP10, and ALK1: An Emerging Vascular Signaling Pathway with Therapeutic Applications. In: Feige, JJ., Pagès, G., Soncin, F. (eds) Molecular Mechanisms of Angiogenesis. Springer, Paris. https://doi.org/10.1007/978-2-8178-0466-8_5

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