September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
c-fos promotes retinal angiogenesis in a mouse model of neovascular AMD
Author Affiliations & Notes
  • Ye Sun
    Department of Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • zhiqiang Lin
    Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Chi-Hsiu Liu
    Department of Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Yan Gong
    Department of Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Raffael Liegl
    Department of Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Thomas Fredrick
    Department of Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Steven Meng
    Department of Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Nicholas Saba
    Department of Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Samuel Burnim
    Department of Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Jing Chen
    Department of Ophthalmology, Boston Children's Hosp/Harvard Med Sch, Boston, Massachusetts, United States
  • Lois E H Smith
    Department of 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; Thomas Fredrick, None; Steven Meng, None; Nicholas Saba, None; Samuel Burnim, None; Jing Chen, None; Lois Smith, None
  • Footnotes
    Support  NIH Grant EY024868; NIH Grant EY017017; NIH Grant P01 HD18655; Lowy Medical Research Institute; European Commission FP7 project 305485 PREVENT-ROP; NIH Grant EY024963; Alcon Research Institute; Mass Lions Eye Research Fund Inc.; Boston Children’s Hospital (BCH) Ophthalmology Foundation;
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4987. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Ye Sun, zhiqiang Lin, Chi-Hsiu Liu, Yan Gong, Raffael Liegl, Thomas Fredrick, Steven Meng, Nicholas Saba, Samuel Burnim, Jing Chen, Lois E H Smith; c-fos promotes retinal angiogenesis in a mouse model of neovascular AMD. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4987.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Abnormal proliferative angiogenesis outside the normal vascular boundaries of the retina in diseases like age-related macular degeneration (AMD) and proliferative diabetic retinopathy, can cause irreversible blindness. The photoreceptor layer is a privileged site, which is normally completely avascular. Any abnormal blood vessels extending into the photoreceptor layer from retinal vessels or choroid, may disrupt the retinal function as is seen in neovascular AMD. However, the mechanisms of maintaining photoreceptor avascularity are not well understood. We identified a novel mechanism by which c-fos controls angiogenesis in the photoreceptor layer mediated through retinal inflammation.

Methods : Very low-density lipoprotein receptor knockout (Vldlr-/-) mice which show pathologic retinal neovascularization in the normally avascular photoreceptor layer, are a valuable model to study the mechanisms of maintaining avascularity in the photoreceptor layer. Laser-capture microdissection, RNA Isolation, 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. Adeno associated virus (AAV) was used to modulate gene expression.

Results : In Vldlr-/- retinas, c-fos mRNA and protein levels were markedly increased during retinal neovascularization development (n=6, P<0.001). Increased c-fos expression was mainly localized to the photoreceptor cell layer where Vldlr is highly expressed. The proinflammatory markers Il6 and Tnf were seen in the same layers as Vldlr and c-fos consistent with a role of Vldlr/c-fos in mediating angiogenic privilege in the retinal photoreceptor cell layer through suppression of proinflammatory cytokines. Suppression of c-fos with AAV expressing shc-fos in the subretinal space and photoreceptor layer prevented neovascularization (reduced 83% compared with control, n=8-10, p<0.001) and leakage. Pharmacologic treatment with a c-fos inhibitor, SR11302 suppressed retinal neovascularization in Vldlr-/- mice.

Conclusions : These data suggest that c-fos mediates neovascularization through control of inflammation in Vldlr-/- retinas indicating synergistic functions of c-FOS and VLDLR in maintaining an avascular photoreceptor layer. Together these findings confirm that inhibition of c-FOS protected against neovascularization.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×