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Bruno Larrivee, Kalonji Ntumba; Role of the BMP9/Alk1 signaling pathway for the prevention of pathological neovascularization.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3650.
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© ARVO (1962-2015); The Authors (2016-present)
Neovascularization (NV) is a pathological feature of some ocular conditions such as age-related macular degeneration (AMD). Conventional therapies are based on the inhibition of VEGF. While anti-VEGF agents have shown good efficacy, a significant proportion of patients show poor responses to these treatments. There is therefore a need to identify complementary targets to inhibit NV in these pathologies. Published studies have shown that the BMP receptor Alk1 is a potent modulator of retinal NV during developmental angiogenesis, but its effects in pathological NV in experimental models of AMD have not been shown. We propose to evaluate the therapeutic potential of Alk1 for the treatment of NV in AMD.
To evaluate the expression of BMP signaling components during pathological angiogenesis, qPCR and immunoblotting were performed on retinas and choroids of mice subjected to oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV).To study the effects of modulating BMP9/Alk1 signaling in experimental models of pathological angiogenesis in the eye (OIR and laser-CNV), we have generated adenoviral constructs to modulate Alk1 signalling. Combination of modulators of Alk1 signaling with anti-VEGF agents were also performed to assess potential synergistic effects.
We have observed an up-regulation of the BMP9 receptors, Alk1 and Endoglin in the endothelium of mice subjected to OIR or laser-induced CNV. In addition, multiple genes associated with BMP signaling were found to be dysregulated. To study the effects of BMP9/Alk1 in retinal pathological angiogenesis, we used adenoviral constructs that can either activate or block Alk1 signaling in vivo. In the OIR, we have observed that pathological neovascularization was reduced in mice receiving BMP9, while mice receiving an Alk1 antagonist (Alk1Fc) displayed a higher frequency of vascular abnormalities such as tufts. BMP9 also reduced CNV in a laser-induced CNV model. Finally, we have observed that BMP9 could enhance the anti-angiogenic activities of compounds blocking VEGF signaling, suggesting that modulators of Alk1 signaling could enhance the efficacy of current anti-angiogenic therapies.
This study suggests an impairment in BMP signaling in the endothelium of mice subjected to OIR or CVN and that modulation of BMP9 signaling can prevent pathological neovascularization in these models.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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