title: BMP9/ALK1 inhibits neovascularization in mouse models of age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in aging populations of industrialized countries. The drawbacks of inhibitors of vascular endothelial growth factor (VEGFs) currently used for the treatment of AMD, which include resistance and potential serious side-effects, require the identification of new therapeutic targets to modulate angiogenesis. BMP9 signaling through the endothelial Alk1 serine-threonine kinase receptor modulates the response of endothelial cells to VEGF and promotes vessel quiescence and maturation during development. Here, we show that BMP9/Alk1 signaling inhibits neovessel formation in mouse models of pathological ocular angiogenesis relevant to AMD. Activating Alk1 signaling in laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) inhibited neovascularization and reduced the volume of vascular lesions. Alk1 signaling was also found to interfere with VEGF signaling in endothelial cells whereas BMP9 potentiated the inhibitory effects of VEGFR2 signaling blockade, both in OIR and laser-induced CNV. Together, our data show that targeting BMP9/Alk1 efficiently prevents the growth of neovessels in AMD models and introduce a new approach to improve conventional anti-VEGF therapies.
authors: Department of Biomedical Sciences, Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Montreal, Quebec, Canada.
authors: Kalonji
authors: K
authors: Ntumba
authors: Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Montreal, Quebec, Canada.
authors: Naoufal
authors: N
authors: Akla
authors: Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA.
authors: S Paul
authors: SP
authors: Oh
authors: Yale Cardiovascular Research Center, New Haven, CT, USA.|Inserm U970, Paris Cardiovascular Research Center, Paris, France.
authors: Anne
authors: A
authors: Eichmann
authors: Department of Biomedical Sciences, Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Montreal, Quebec, Canada.|Department of Molecular Biology, Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Montreal, Quebec, Canada.|Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Montreal, Quebec, Canada.|Department of Biological Sciences, Université du Québec à Montréal, Montréal, Quebec, Canada.
authors: Bruno
authors: B
authors: Larrivée
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000473:pathology*; D000818:Animals; D020256:Choroidal Neovascularization / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors / Q000235:genetics; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008268:Macular Degeneration / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012164:Retinal Diseases / Q000473:pathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse
keywords: BMP signaling; Gerotarget; age-related macular degeneration; angiogenesis; ocular pathologies