BMP9 and BMP10 are critical for postnatal retinal vascular remodeling

ALK1 is a type I receptor of the TGF-β family that is involved in angiogenesis. Circulating BMP9 was identified as a specific ligand for ALK1 inducing vascular quiescence. In this work, we found that blocking BMP9 with a neutralizing antibody in newborn mice significantly increased retinal vascular...

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Bibliographic Details
Published in:Blood 2012-06, Vol.119 (25), p.6162-6171
Main Authors: Ricard, Nicolas, Ciais, Delphine, Levet, Sandrine, Subileau, Mariela, Mallet, Christine, Zimmers, Teresa A., Lee, Se-Jin, Bidart, Marie, Feige, Jean-Jacques, Bailly, Sabine
Format: Article
Language:English
Subjects:
Activin Receptors, Type I - chemistry
Activin Receptors, Type I - pharmacology
Activin Receptors, Type II
Animals
Animals, Newborn
Antibodies - pharmacology
Biological and medical sciences
Bone Morphogenetic Proteins - genetics
Bone Morphogenetic Proteins - metabolism
Bone Morphogenetic Proteins - physiology
Cell Count
Cells, Cultured
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Endothelium, Vascular - physiology
Growth Differentiation Factor 2 - antagonists & inhibitors
Growth Differentiation Factor 2 - genetics
Growth Differentiation Factor 2 - metabolism
Growth Differentiation Factor 2 - physiology
Hematologic and hematopoietic diseases
Humans
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Neovascularization, Pathologic - chemically induced
Neovascularization, Pathologic - genetics
Neovascularization, Pathologic - metabolism
NIH 3T3 Cells
Protein Structure, Tertiary
Recombinant Proteins - pharmacology
Retinal Vessels - cytology
Retinal Vessels - drug effects
Retinal Vessels - metabolism
Retinal Vessels - physiology
Vascular Biology
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Summary:ALK1 is a type I receptor of the TGF-β family that is involved in angiogenesis. Circulating BMP9 was identified as a specific ligand for ALK1 inducing vascular quiescence. In this work, we found that blocking BMP9 with a neutralizing antibody in newborn mice significantly increased retinal vascular density. Surprisingly, Bmp9-KO mice did not show any defect in retinal vascularization. However, injection of the extracellular domain of ALK1 impaired retinal vascularization in Bmp9-KO mice, implicating another ligand for ALK1. Interestingly, we detected a high level of circulating BMP10 in WT and Bmp9-KO pups. Further, we found that injection of a neutralizing anti-BMP10 antibody to Bmp9-KO pups reduced retinal vascular expansion and increased vascular density, whereas injection of this antibody to WT pups did not affect the retinal vasculature. These data suggested that BMP9 and BMP10 are important in postnatal vascular remodeling of the retina and that BMP10 can substitute for BMP9. In vitro stimulation of endothelial cells by BMP9 and BMP10 increased the expression of genes involved in the Notch signaling pathway (Jagged1, Dll4, Hey1, Hey2, Hes1) and decreased apelin expression, suggesting a possible cross-talk between these pathways and the BMP pathway.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2012-01-407593