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Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy

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Abstract

Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy.

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Acknowledgments

We thank Molly R. Seaward, Keirnan L. Willett, Roberta J. Dennison, Nathan M. Krah for their technical assistance. This work was supported by Charles H. Hood Foundation, Boston Children’s Hospital (BCH) Ophthalmology Foundation, BCH Manton Center for Orphan Disease Research, Blind Childrens Center, BrightFocus Foundation, Mass Lions Eye Research Fund Inc. and BCH Career Development Award (to JC), NIH (EY017017, EY022275, PO1 HD18655), V. Kann Rasmussen Foundation, RPB Senior Investigator Award, Alcon Research Institute Award, and the Lowy Medical Research Instiute (LEHS). AS is supported by the Freifrau von Nauendorff Foundation and the German Ophthalmic Society. DAS is supported by the Paul F. Glenn Foundation, NIH (RO1AG019719), JDRF, and the United Mitochondrial Disease Foundation. PS holds a Canada Research Chair in Retinal Cell Biology. PS and JSJ are supported by the Canadian Institutes of Health Research. SM is supported by the Consejo Nacional de Ciencia y Tecnología, Mexico (CONACyT 177819).

Conflict of interest

DAS is a consultant to and inventor on patents licensed to GlaxoSmithKline and Ovascience.

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Authors and Affiliations

  1. Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Jing Chen, Aimee M. Juan, Christian G. Hurst, Colman J. Hatton, Dorothy T. Pei, Jean-Sebastien Joyal, Lucy P. Evans, Zhenghao Cui, Andreas Stahl, Przemyslaw Sapieha & Lois E. H. Smith

  2. Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Jing Chen & Aimee M. Juan

  3. Instituto Nacional de Geriatría, Institutos Nacionales de Salud, Mexico, Mexico

    Shaday Michan

  4. University Eye Hospital Freiburg, Freiburg, Germany

    Andreas Stahl

  5. Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Canada

    Przemyslaw Sapieha

  6. Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA, USA

    David A. Sinclair

  7. Department of Pharmacology, The University of New South Wales, Paddington, Australia

    David A. Sinclair

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  1. Jing Chen
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  2. Shaday Michan
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  3. Aimee M. Juan
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Corresponding authors

Correspondence to Jing Chen or Lois E. H. Smith.

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Chen, J., Michan, S., Juan, A.M. et al. Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy. Angiogenesis 16, 985–992 (2013). https://doi.org/10.1007/s10456-013-9374-5

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  • DOI: https://doi.org/10.1007/s10456-013-9374-5

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