March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Microrna-132 Antagonism Potently Limits Neovascularization In Multiple Disease Models
Author Affiliations & Notes
  • Peter D. Westenskow
    Cell Biology, Scripps Research Institute, La Jolla, California
  • Toshihide Kurihara
    Cell Biology, Scripps Research Institute, La Jolla, California
  • Lea Scheppke
    Cell Biology, Scripps Research Institute, La Jolla, California
  • Stacey Moreno
    Cell Biology, Scripps Research Institute, La Jolla, California
  • Edith Aguilar
    Cell Biology, Scripps Research Institute, La Jolla, California
  • Sudarshan Anand
    Moores UCSD Cancer Center, UCSD, San Diego, California
  • Iacovos Michael
    Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  • Andras Nagy
    Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  • David A. Cheresh
    Moores UCSD Cancer Center, UCSD, San Diego, California
  • Martin Friedlander
    Cell Biology, Scripps Research Institute, La Jolla, California
  • Footnotes
    Commercial Relationships  Peter D. Westenskow, None; Toshihide Kurihara, None; Lea Scheppke, None; Stacey Moreno, None; Edith Aguilar, None; Sudarshan Anand, None; Iacovos Michael, None; Andras Nagy, None; David A. Cheresh, None; Martin Friedlander, None
  • Footnotes
    Support  NIH grant EY11254
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 4120. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: retinal neovascularization • gene modifiers • vascular endothelial growth factor 
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