September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Disruption of astrocytic gap junctions promotes revascularization and diminishes abnormal vessel growth in oxygen-induced retinopathy
Author Affiliations & Notes
  • NEFELI SLAVI
    Biological and Vision Sciences, SUNY College of Optometry, New York, New York, United States
  • Jessica Ackert
    Biological and Vision Sciences, SUNY College of Optometry, New York, New York, United States
  • Heike Wulff
    Pharmacology, University of California, Davis, California, California, United States
  • Miduturu Srinivas
    Biological and Vision Sciences, SUNY College of Optometry, New York, New York, United States
  • Footnotes
    Commercial Relationships   NEFELI SLAVI, None; Jessica Ackert, None; Heike Wulff, None; Miduturu Srinivas, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3657. doi:
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      NEFELI SLAVI, Jessica Ackert, Heike Wulff, Miduturu Srinivas; Disruption of astrocytic gap junctions promotes revascularization and diminishes abnormal vessel growth in oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3657.

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

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Abstract

Purpose : Proliferative ischemic retinopathies are a leading cause of blindness. Limitations associated with the currently available treatments necessitate the identification of alternative interventions. Gap junction channels composed of connexin 43 (Cx43) extensively couple the retinal astrocytic network and might contribute to the loss of astrocytes, an event that has been correlated with abnormal vessel growth. Here, we examine whether absence of astrocytic coupling provided by Cx43 reverses the pathological changes associated with oxygen-induced retinopathy (OIR).

Methods : The effect of genetic ablation of Cx43 and of pharmacological inhibition of Cx43 channels was studied in a mouse model of OIR. Conditional knockout (KO) of Cx43 from astrocytes was established using the Cre-loxP recombination system by means of a GFAP promoter to drive Cre expression. Wild type (WT) and KO litters were exposed to 75% oxygen from postnatal day (p) 7 to p12 and then returned to room air. For pharmacological experiments pups were given intravitreal injections of SBO15, a Cx43 inhibitor recently developed in our laboratory. On p17, retinal whole-mounts were stained with isolectin and the degrees of vasobliteration and neovascularization were quantified. Student’s t-test was used for statistical analyses.

Results : The avascular retinal area (VO) and the formation of neovascular tufts (NV) at p17 were significantly reduced in astrocytic Cx43 KO mice compared to WT littermates (decrease of 52±9%, p=0.01 in VO and 54.4±8.3%, p=0.03 in NV; N=5). Similarly, SBO15 (20µM) accelerated retinal revascularization and prevented the development of neovascularization (decrease of 57.3±8.1%, p=0.0009 in VO and 78.9±6.3%, p<0.0001 in NV; N=6). The absence of Cx43 coupling did not affect normal vascular development and the layered structured of the retina in room air-raised mice.

Conclusions : Our results indicate that Cx43-mediated astrocytic coupling plays an important role in the progression of ocular neovascular diseases. Inhibition of Cx43 channels is a potentially useful strategy to suppress retinal neovascularization. Whether Cx43 coupling causes pathological neovascularization by mediating astrocytic degeneration is being investigated.

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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