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Trans-NIH Angiogenesis Workshop; May 20-21, 2013
  • Abstracts

    miR Regulation of the Angiogenic Response

    David Cheresh, PhD  [ View bio ]
    (University of California, San Diego)

    During development, pro- and anti-angiogenic factors orchestrate a complex, dynamic process to allow initial sprouting and invasion, subsequent pruning and remodeling, and finally maturation and survival of blood vessels. However, in pathological conditions such as cancer, diabetic retinopathy, macular degeneration or inflammation the same angiogenic signaling pathways are misregulated and exploited, typically resulting in poorly organized vessels with leaky and tortuous properties. In the last decade, a new class of small non-coding RNA molecules termed microRNAs (miRs) have emerged as key regulators of angiogenesis

    We recently identified miR-132 as a regulator of pathological neovascularization that was highly expressed in activated blood vessels, but was undetectable in normal endothelium. Ectopic expression of miR-132 in endothelial cells increased their proliferation and tube-forming capacity, whereas intraocular injection of an antagomir targeting miR-132, reduced postnatal retinal vascular development in mice. We identified p120RasGAP as a miR-132 target and showed that miR-132 and p120RasGAP are expressed reciprocally during pathological angiogenesis. Our observations in several in vitro and in vivo models suggest that miR-132 acts as an angiogenic switch by suppressing endothelial p120RasGAP expression, leading to Ras activation and the induction of neovascularization, whereas the application of anti–miR-132 inhibits neovascularization by maintaining vessels in the resting state.

    In contrast to miR-132, a highly upregulated miR that promotes angiogenesis, we have identified miR-103 as a negative regulator of angiogenesis. microRNA-103 is an apoptomiR that is induced by high dose radiation and other DNA damaging agents in endothelial cells. Functionally, miR-103 mimics genotoxic stress and causes DNA double strand breaks leading to cell death and decreased angiogenesis. Mechanistically, miR-103 targets DNA repair pathway components – the exonuclease TREX1 and the adaptor FANCF. Our data uncovers a microRNA mediated pathway of DNA damage unique to proliferating endothelium that can be exploited for radiosensitization of tumor vasculature.

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Workshop Organizer: NIH

NCI:Nancy Emenaker, PhD, RD
Suzanne Forry-Schaudies, PhD
NHLBI:Yunling Gao, MD, PhD
NIDDK: Teresa Jones, MD

NIH - National Institutes of Health: Turning Discovery Into Health

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