title: Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation.
abstract: Lymphatic vessels are critical for the maintenance of tissue fluid homeostasis and their dysfunction contributes to several human diseases. The activin receptor-like kinase 1 (ALK1) is a transforming growth factor-β family type 1 receptor that is expressed on both blood and lymphatic endothelial cells (LECs). Its high-affinity ligand, bone morphogenetic protein 9 (BMP9), has been shown to be critical for retinal angiogenesis. The aim of this work was to investigate whether BMP9 could play a role in lymphatic development. We found that Bmp9 deficiency in mice causes abnormal lymphatic development. Bmp9-knockout (KO) pups presented hyperplastic mesenteric collecting vessels that maintained LYVE-1 expression. In accordance with this result, we found that BMP9 inhibited LYVE-1 expression in LECs in an ALK1-dependent manner. Bmp9-KO pups also presented a significant reduction in the number and in the maturation of mesenteric lymphatic valves at embryonic day 18.5 and at postnatal days 0 and 4. Interestingly, the expression of several genes known to be involved in valve formation (Foxc2, Connexin37, EphrinB2, and Neuropilin1) was upregulated by BMP9 in LECS. Finally, we demonstrated that Bmp9-KO neonates and adult mice had decreased lymphatic draining efficiency. These data identify BMP9 as an important extracellular regulator in the maturation of the lymphatic vascular network affecting valve development and lymphatic vessel function.
authors.affiliation: INSERM U1036, Grenoble, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Levet
authors.forename: Delphine
authors.initials: D
authors.lastname: Ciais
authors.forename: Galina
authors.initials: G
authors.lastname: Merdzhanova
authors.forename: Christine
authors.initials: C
authors.lastname: Mallet
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Zimmers
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Fabrice P
authors.initials: FP
authors.lastname: Navarro
authors.forename: Isabelle
authors.initials: I
authors.lastname: Texier
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.forename: Sabine
authors.initials: S
authors.lastname: Bailly
authors.forename: Daniel
authors.initials: D
authors.lastname: Vittet
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics* / Q000502:physiology; D042601:Lymphatic Vessels / Q000378:metabolism / Q000502:physiology*; D026901:Membrane Transport Proteins; D008643:Mesentery / Q000196:embryology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D006023:Glycoproteins; D055427:Growth Differentiation Factor 2; D026901:Membrane Transport Proteins; C526108:Gdf2 protein, mouse; C492273:LYVE1 protein, mouse