Research Papers: Gerotarget (Focus on Aging):
BMP9/ALK1 inhibits neovascularization in mouse models of age-related macular degeneration
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Kalonji Ntumba1, Naoufal Akla2, S. Paul Oh5, Anne Eichmann6,7 and Bruno Larrivée1,3,4,8
1 Department of Biomedical Sciences, Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Montreal, Quebec, Canada
2 Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Montreal, Quebec, Canada
3 Department of Molecular Biology, Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Montreal, Quebec, Canada
4 Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Montreal, Quebec, Canada
5 Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA
6 Yale Cardiovascular Research Center, New Haven, CT, USA
7 Inserm U970, Paris Cardiovascular Research Center, Paris, France
8 Department of Biological Sciences, Université du Québec à Montréal, Montréal, Quebec, Canada
Bruno Larrivée, email:
Keywords: age-related macular degeneration, ocular pathologies, angiogenesis, BMP signaling, Gerotarget
Received: April 20, 2016 Accepted: July 13, 2016 Published: August 10, 2016
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.
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