Bone morphogenetic protein-9 is a circulating vascular quiescence factor.
Angiogenesis is a complex process, requiring a finely tuned balance between numerous stimulatory and inhibitory signals. ALK1 (activin receptor like-kinase 1) is an endothelial-specific type 1 receptor of the transforming growth factor-beta receptor family. Heterozygotes with mutations in the ALK1 gene develop hereditary hemorrhagic telangiectasia type 2 (HHT2). Recently, we reported that bone morphogenetic protein (BMP)9 and BMP10 are specific ligands for ALK1 that potently inhibit microvascular endothelial cell migration and growth. These data lead us to suggest that these factors may play a role in the control of vascular quiescence. To test this hypothesis, we checked their presence in human serum. We found that human serum induced Smad1/5 phosphorylation. To identify the active factor, we tested neutralizing antibodies against BMP members and found that only the anti-BMP9 inhibited serum-induced Smad1/5 phosphorylation. The concentration of circulating BMP9 was found to vary between 2 and 12 ng/mL in sera and plasma from healthy humans, a value well above its EC(50) (50 pg/mL). These data indicated that BMP9 is circulating at a biologically active concentration. We then tested the effects of BMP9 in 2 in vivo angiogenic assays. We found that BMP9 strongly inhibited sprouting angiogenesis in the mouse sponge angiogenesis assay and that BMP9 could inhibit blood circulation in the chicken chorioallantoic membrane assay. Taken together, our results demonstrate that BMP9, circulating under a biologically active form, is a potent antiangiogenic factor that is likely to play a physiological role in the control of adult blood vessel quiescence.
David
Laurent
L
Institut National de la Santé et de la Recherche Médicale, U878, Grenoble, France.
Mallet
Christine
C
Keramidas
Michelle
M
Lamandé
Noël
N
Gasc
Jean-Marie
JM
Dupuis-Girod
Sophie
S
Plauchu
Henri
H
Feige
Jean-Jacques
JJ
Bailly
Sabine
S
D016475:3T3 Cells; D030301:Activin Receptors, Type II / Q000235:genetics / Q000502:physiology*; D000328:Adult; D042501:Angiogenic Proteins; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000502:physiology*; D016022:Case-Control Studies; D002642:Chick Embryo; D005260:Female; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D051785:Smad Proteins / Q000378:metabolism; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000097:blood / Q000235:genetics; D014162:Transfection
D042501:Angiogenic Proteins; D019485:Bone Morphogenetic Proteins; C525887:GDF2 protein, human; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D051785:Smad Proteins; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II