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Blood, 1 March 2007, Vol. 109, No. 5, pp. 1953-1961.
Prepublished online as a Blood First Edition Paper on October 26, 2006; DOI 10.1182/blood-2006-07-034124.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells
Laurent David1,2,3,
Christine Mallet1,2,3,
Sabine Mazerbourg4,
Jean-Jacques Feige1,2,3, and
Sabine Bailly1,2,3
1 Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe Mixte INSERM (EMI 01-05), Grenoble, France;
2 Commissariat à l'Energie Atomique (CEA), Département Réponse et Dynamique Cellulaires (DRDC)/ANGIO, Grenoble, France;
3 Université Joseph Fourier, Grenoble, France;
4 Université Henri Poincaré, Nancy 1, Unité Propre de Recherche et d'Enseignement Supérieur (UPRES) Equipe Associée (EA) 3442, Vandoeuvre les Nancy, France
ALK1 is an endothelial-specific type I receptor of the TGFß receptor family whose heterozygous mutations cause hereditary hemorrhagic telangiectasia type 2. Although TGFß1 and TGFß3 have been shown to bind ALK1 under specific experimental conditions, they may not represent the physiological ligands for this receptor. In the present study, we demonstrate that BMP9 induces the phosphorylation of Smad1/5/8 in microvascular endothelial cells, and this phosphorylation lasts over a period of 24 hours. BMP9 also activates the ID1 promoterderived BMP response element (BRE) in a dose-dependent manner (EC50 = 45 ± 27 pg/mL), and this activation is abolished by silencing ALK1 expression or addition of ALK1 extracellular domain. Overexpression of endoglin increases the BMP9 response, whereas silencing of both BMPRII and ActRIIA expressions completely abolishes it. BMP10, which is structurally close to BMP9, is also a potent ALK1 ligand. Finally, we demonstrate that BMP9 and BMP10 potently inhibit endothelial cell migration and growth, and stimulate endothelial expression of a panel of genes that was previously reported to be activated by the constitutively active form of ALK1. Taken together, our results suggest that BMP9 and BMP10 are two specific ALK1 ligands that may physiologically trigger the effects of ALK1 on angiogenesis.

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