BMP9 and BMP10 are critical for postnatal retinal vascular remodeling

• Published in: Blood Vol. 119; no. 25; pp. 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: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 21.06.2012; Americain Society of Hematology; American Society of Hematology
• 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; Eye; Vascular remodeling; Visual system; Postnatal; Hematology; Retina; Bone morphogenetic protein 9
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-01-407593

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.