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Oncotarget: BMP9/ALK1 inhibits neovascularization


FOR IMMEDIATE RELEASE
2020-12-07

Here is a link to a video interview with Dr. Burno Larrivee about this research on the Oncotarget YouTube Channel

Oncotarget published "BMP9/ALK1 inhibits neovascularization in mouse models of age-related macular degeneration" which reported that the drawbacks of inhibitors of vascular endothelial growth factor 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, the researchers 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 and oxygen-induced retinopathy 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, the data in this Oncotarget study shows that targeting BMP9/Alk1 efficiently prevents the growth of neovessels in AMD models and introduce a new approach to improve conventional anti-VEGF therapies.

This Oncotarget study shows that targeting BMP9/Alk1 efficiently prevents the growth of neovessels in AMD models and introduce a new approach to improve conventional anti-VEGF therapies.

Dr. Bruno Larrivée from The University of Montreal said, "AMD is the leading cause of blindness in the aging populations of western industrialized countries."

Wet AMD accounts for about 10-20% of AMD cases, but is responsible for 80-90% of the severe loss of central vision associated with AMD. This advanced form is characterized by pathological choroidal neovascularization below the retinal pigmented epithelium or in the subretinal space.

It represents a contributory factor in the initiation of angiogenesis as it directs the migration of the tip cell, a specialized endothelial cells that guides vessel outgrowth towards hypoxic or inflamed tissue and leads EC stalk cells forming the capillary lumen.

The tip/stalk phenotype is controlled by the expression of the Notch ligand Dll4 in tip cells exposed to a VEGF gradient, triggering Notch activation in adjacent cells.

Figure 6: Effects of BMP9 and VEGFR2 blockade on CNV. A. Phalloidin (red) and IsoB4 staining of choroid-sclera complexes two weeks after laser burn and treatment with adenoviral particles. B. Quantification of neovascular area following laser-burn (n = 4 animals/group). All histograms represent mean ± standard error of the mean. **P < 0.01, ***P < 0.005. Scale bar: 75 μm.

These differential signaling events further ensure the selection of the initial Notch-inactive cell as a single tip cell leading the neovesssels as opposed to the Notch-active stalk cells forming the base of the sprout .

Alk1 and Alk5 signaling are suppressed in tip cells through the guidance receptor Neuropilin-1, but signal in stalk cells in cooperation with Notch to promote stalk cell behavior.

The Larrivée Research Team concluded in their Oncotarget Research Paper, "results from the current study reveal BMP9 as an effective and potent inhibitor of pathological neovascularization associated with wet AMD. Moreover, BMP9 agonists represent promising complements that would lower the conventional dose of anti-VEGF agents required to achieve an equivalent therapeutic index. Thus, BMP9 and anti-VEGF combined therapies would limit the aforementioned adverse effects commonly associated with VEGF inhibitors."

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DOI - https://doi.org/10.18632/oncotarget.11182

Full text - https://www.oncotarget.com/article/11182/text/

Correspondence to - Bruno Larrivée- bruno.larrivee@umontreal.ca

Keywords - age-related macular degeneration, ocular pathologies, angiogenesis, BMP signaling, Gerotarget

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