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Peter D. Westenskow, Toshihide Kurihara, Lea Scheppke, Stacey Moreno, Edith Aguilar, Sudarshan Anand, Iacovos Michael, Andras Nagy, David A. Cheresh, Martin Friedlander; Microrna-132 Antagonism Potently Limits Neovascularization In Multiple Disease Models. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4120.
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MicroRNAs (miRs) can be activated by various stimuli to refine the activity of molecular signaling pathways. We recently reported that miR-132 directly negatively regulates RasGAP to drive vascular proliferation. In the eye, anti-miR-132 injections severely retard ocular angiogenesis. If miR-132 also controls pathological angiogenesis anti-miR-132 therapies may be useful for treating multiple blinding disorders in humans.pathological angiogenesis anti-miR-132 therapies may be useful for treating multiple blinding disorders in humans.
We utilized RT-PCR, in-situ hybridization, and immunohistochemistry to measure levels of miR-132 and RasGAP expression during development and in two relevant animal disease models, oxygen-induced retinopathy (OIR) and VLDLR-/- mice. Anti-miR-132 was injected intravitreally to determine if progression of each of these conditions could be limited. The functions of anti-miR-132 were directly compared with a potent anti-angiogenic VEGF-trap in each model. We also utilized microarrays and multiplex ELISAs to determine if any off-target or compensatory effects may be induced by targeting miR-132.
We demonstrate in this study that miR-132 and RasGAP have inverse expression patterns during critical early postnatal stages of retinal angiogenesis. In both models of pathological angiogenesis we determine that miR-132 expression is dysregulated; injections of anti-miR-132 restore RasGAP to normal levels and very effectively prevent significant neovascularization. Furthermore, in our studies anti-miR-132 consistently outperforms VEGF-trap at limiting neovascularization. Lastly, both the microarray and ELISA results demonstrate that significantly more compensatory pro-angiogenic genes and proteins are upregulated due to VEGF-trap injections than by anti-miR-132.
We demonstrate that miR-132 controls normal and pathological ocular angiogenesis. Injections of anti-miR-132 limit neovascularization in OIR and VLDLR-/- mice more effectively than VEGF-trap. Additionally, anti-miR-132 appears to induce fewer off-target effects and limits compensatory upregulation of several other pro-angiogenic factors. Therefore, these results provide a strong molecular basis for targeting miR-132 as a novel anti-angiogenic therapeutic strategy.
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