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.
Highlights
Age-related macular degeneration (AMD) is the leading cause of blindness in the aging populations of western industrialized countries [1]
To evaluate the involvement of BMP9 signaling in pathological angiogenesis in the retina, we first examined the expression of genes involved in BMP9 signaling in retinal ECs from mice subjected to oxygen-induced retinopathy (OIR)
Transcripts corresponding to Bone Morphogenetic Proteins (BMPs) receptors (Alk1, Alk2, Alk3, BMPR2 and Endoglin) were detected in both groups, but levels of activin receptor-like kinase 1 (Alk1) were significantly increased in OIR retinas compared to controls, suggesting differential use during pathological retinal angiogenesis (Figure 1A)
Summary
AMD is the leading cause of blindness in the aging populations of western industrialized countries [1]. To evaluate the involvement of BMP9 signaling in pathological angiogenesis in the retina, we first examined the expression of genes involved in BMP9 signaling in retinal ECs from mice subjected to oxygen-induced retinopathy (OIR). Transcripts corresponding to BMP receptors (Alk1, Alk2, Alk3, BMPR2 and Endoglin) were detected in both groups, but levels of Alk1 were significantly increased in OIR retinas compared to controls, suggesting differential use during pathological retinal angiogenesis (Figure 1A).
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