June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Inflammatory signals from photoreceptor modulate pathological retinal angiogenesis via c-Fos
Author Affiliations & Notes
  • Ye Sun
    Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Zhiqiang Lin
    Cardiology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Chi-Hsiu Liu
    Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Yan Gong
    Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Raffael Liegl
    Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Steven Meng
    Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Samuel Burnim
    Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Zhongxiao Wang
    Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • James D Akula
    Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Jing Chen
    Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Lois E H Smith
    Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Ye Sun, None; Zhiqiang Lin, None; Chi-Hsiu Liu, None; Yan Gong, None; Raffael Liegl, None; Steven Meng, None; Samuel Burnim, None; Zhongxiao Wang, None; James Akula, None; Jing Chen, None; Lois Smith, None
  • Footnotes
    Support  NH gant EY024864, EY022275, EY017017, P01 HD18655, EY024963
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 2451. doi:
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    • Get Citation

      Ye Sun, Zhiqiang Lin, Chi-Hsiu Liu, Yan Gong, Raffael Liegl, Steven Meng, Samuel Burnim, Zhongxiao Wang, James D Akula, Jing Chen, Lois E H Smith; Inflammatory signals from photoreceptor modulate pathological retinal angiogenesis via c-Fos. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2451.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Pathological neovessels grow into the normally avascular photoreceptors causing vision loss in many eye diseases such as age-related macular degeneration and macular telangiectasia, and the signals that regulate avascular privilege and their localization to photoreceptors are unknown. We identified a novel pathway by which c-Fos controls angiostasis/angiogenesis in the photoreceptor layer mediated through inflammatory signals in photoreceptors.

Methods : Very low-density lipoprotein receptor knockout (Vldlr -/-) mice, which develop pathological retinal and choroidal neovascularization in photoreceptor layer, were used as a mouse model. Vldlr +/- was used to generate littermate Vldlr -/- and Vldlr +/+. Real-time PCR, western blot and immunohistochemistry were used to analyze gene expression and protein localization. Confocal imaging, fundus fluorescein angiography and HE staining were used to identify phenotypes. Neovascularization was quantified using image J. Adeno-associated virus (AAV) was subretinally injected into postnatal day 1 (P1) mouse and retinas were collected at P16 for phenotype analysis. ERG was used to demonstrate the function of photoreceptor cells in mice. Results are presented as mean ± SEM and were compared using the 2-tailed unpaired t-test. Statistical analyses were performed with GraphPad Prism (v6.0).

Results : Vldlr -/- photoreceptors with violation of avascular privilege had increased c-Fos by ~5 fold at mRNA level at P12 (p≤0.001, n=8), which induced inflammatory cytokines IL6 and TNFa, leading to activation of STAT3 and increased TNFAIP3. IL6-Activated STAT3 increased photoreceptor VEGFA directly. Elevated TNFAIP3 activated STAT3, which also increased VEGFA indirectly by suppressing SOCS3 expression. VEGF then induced neovascularization, breaching the avascular zone. Inhibition of c-Fos using photoreceptor specific AAV-sh_c-fos substantially reduced the pathological neovascularization by 75% (p≤0.001, n=10) at P16 invading photoreceptors and rescued visual function in Vldlr -/- mice. Pharmacologic treatment with a c-Fos inhibitor, SR11302 suppressed retinal neovascularization by 48% in Vldlr -/- mice (p≤0.001, n=6) at P16.

Conclusions : These findings suggested that photoreceptor c-Fos controls blood vessel growth into the normally avascular photoreceptor layer through the inflammatory signal-induced STAT3/VEGFA pathway.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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