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Targeting BMP signaling for the treatment of neovascular age‐related macular degeneration
Author(s) -
Larrivee Bruno,
Ntumba Kalonji
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.85.1
Subject(s) - choroidal neovascularization , macular degeneration , neovascularization , angiogenesis , medicine , cancer research , signal transduction , receptor , endoglin , endothelium , pharmacology , biology , microbiology and biotechnology , ophthalmology , stem cell , cd34
The majority of current vascular‐directed treatments for pathologies such as Age‐Related Macular Degeneration (AMD) or cancer target the VEGFR pathway to induce the quiescence of the vasculature network. However, they use frequent or high doses of drugs resulting in local or systemic secondary effects and are only partially effective in some patients. Therefore, treatments targeting additional anti‐angiogenic pathways are presently needed to improve conventional therapies and efficiently treat vascular‐related pathologies. We hypothesize that current AMD treatments may be improved by combining anti‐VEGF treatment with therapies that target additional signaling pathways that promote vessel quiescence. We are therefore investigating the therapeutic potential of BMP9 and its receptor Alk1 for AMD. We have observed an up‐regulation of the BMP9 receptors, Alk1 and Endoglin in the endothelium of mice subjected to oxygen‐induced retinopathy (OIR) or laser‐induced choroidal neovascularization (CNV). In addition, multiple genes associated with BMP signaling were found to be dysregulated in these models. To study the effects of BMP9/Alk1 in retinal pathological angiogenesis, we have generated adenoviral constructs that can either activate or block Alk1 signaling in vivo. 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. 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.