September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Ferrochelatase is required for retinal neovascularization
Author Affiliations & Notes
  • Halesha Dhurvigere Basavarajappa
    Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States
    Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Lynn C Shaw
    Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Sergio Li Calzi
    Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Kamakshi Sishtla
    Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Maria B Grant
    Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Timothy William Corson
    Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States
    Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Footnotes
    Commercial Relationships   Halesha Basavarajappa, US Provisional 62/111,149 (P); Lynn Shaw, None; Sergio Calzi, None; Kamakshi Sishtla, None; Maria Grant, None; Timothy Corson, US Provisional 62/111,149 (P)
  • Footnotes
    Support  International Retinal Research Foundation, Retina Research Foundation, Research to Prevent Blindness, NIH grants EY0126001, EY007739, HL110170
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3639. doi:
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      Halesha Dhurvigere Basavarajappa, Lynn C Shaw, Sergio Li Calzi, Kamakshi Sishtla, Maria B Grant, Timothy William Corson; Ferrochelatase is required for retinal neovascularization. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3639.

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

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Abstract

Purpose : Despite the power of anti-vascular endothelial growth factor (VEGF) therapies, there remains a need for novel therapeutic targets in retinopathy of prematurity, a major cause of blindness in infants. We previously identified the heme biosynthesis enzyme ferrochelatase (Fech) as crucial for angiogenesis in vitro and in the laser-induced choroidal neovascularization model. Here, we tested the hypothesis that Fech knockdown would reduce neovascularization in the murine oxygen-induced retinopathy (OIR) model of retinopathy of prematurity.

Methods : OIR was induced in neonatal mice by a standard method of exposure to 75% O2 hyperoxia at postnatal day (P) 7 followed by return to normoxia at P12. Fech or non-targeting siRNA or vehicle was injected intravitreally at P12, and retinal wholemounts prepared at P17. Collagen IV staining followed by manual analysis revealed areas of vasoobliteration and neovascularization, which were compared by ANOVA with Tukey’s post hoc tests.

Results : Fech knockdown dose-dependently reduced neovascular area to near zero at high (1.6 µM) concentrations (1.5 ± 0.3% vs. 19.9 ± 0.7% for vehicle control, p=1.02x10-8). Knockdown also modestly but significantly reduced vasoobliteration at all tested concentrations (15.2 ± 1.2% at 1.6 µM siRNA vs. 20.5 ± 0.7% for vehicle control, p=0.006). No disruption of normal vasculature or other acute toxicity was observed.

Conclusions : The knockdown of Fech profoundly decreased neovascularization in the OIR model, without obvious toxic effects. Taken together with the in vitro significance of Fech for angiogenesis and its importance for choroidal neovascularization, inhibition of Fech emerges as a very appealing, VEGF-independent therapeutic avenue for ocular neovascularization.

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

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