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Laurent David

Identification of ALK1 ligand (activin receptor like kinase 1): BMP9. A new circulating regulator of the endothelial quiescence

Published on 31 October 2007


Thesis presented October 31, 2007

Abstract:
Activin receptor-like kinase 1 (ALK1) is a type 1 receptor of the TGFß receptor family. In contrast to other receptors of the same family, ALK1 expression is mostly restricted to endothelial cells. This receptor has been implicated in angiogenesis by in vivo studies: (1) mutations in ALK1 are implicated in hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vascular dysplasia; (2) mouse embryos lacking ALK1 die by midgestation; (3) the zebrafish mutant ALK1 has an abnormal circulation pattern. Together, these studies clearly demonstrate that ALK1 is required for angiogenesis.
Since the natural ligand for ALK1 has not been conclusively identified, ALK1 functions in endothelial cells remain unclear. Several groups have studied ALK1 functions using a constitutively activated form of ALK1 but those studies gave opposite results. In 2002, TGFß1 and 3 have been described as activators of ALK1 but this model presents several incoherencies, particularly by the fact that TGFß do not mimic the effects of ALK1. Moreover, it has been described that another ligand for ALK1 was present in the human serum. Those results suggest that a specific ligand for ALK1, yet unidentified, might exists.
Our aim was to identify this ligand. I also investigated the ALK1 signaling pathway.
In this thesis, we demonstrate that BMP9 and BMP10 are ligands for ALK1. Those ligands signal via a receptor complex made of ALK11, and BMPR2 or ActR2A as type II receptors. We also show that endoglin could increase ALK1 activation by BMP9 and BMP10.
We bring several new clues of ALK1 involvement in the maturation phase of angiogenesis: (1) ALK1 silencing in human microvascular endothelial cells increase their migration, (2) BMP9 and BMP10 inhibit the proliferation and the migration of endothelial cells in vitro and (3) BMP9 inhibits angiogenesis in vivo in several models.
Moreover, we determine that BMP9 circulates both in plasma and serum. This strongly suggests that BMP9 might be a physiological ligand for ALK1, and might act as an endothelial quiescence factor.
In parallel, we determined that ALK1 inhibits endothelial cells migration by a Smad-independent pathway, by inhibiting JNK and ERK pathways.
In this thesis, we identified the first physiological ligand of ALK1: BMP9 and we confirmed ALK1 involvement in the maturation phase of angiogenesis. Our results suggest that BMP9 is a new circulating regulator of angiogenesis. This finding will also allow a much better understanding of ALK1 functions and mechanisms of action.

Keywords:
ALK1, endothelial​ cells, angiogenesis, BMP9, BMP10