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NEFELI SLAVI, Miduturu Srinivas, Suresh Viswanathan; Inhibition of Cx43 phosphorylation in astrocytes restores neuronal function in oxygen-induced retinopathy. . Invest. Ophthalmol. Vis. Sci. 2018;59(9):3584. doi: https://doi.org/.
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Cx43, a protein that forms gap junction channels in astrocytes, negatively influences directional angiogenesis in oxygen-induced retinopathy (OIR) (Slavi et al. ARVO 2017). Conversely, suppression of Cx43 channel function in both conditional Cx43 knockout (KO) and site-specific phosphorylation-deficient (KI) mice promotes vascular regeneration in the hypoxic retina. In OIR, vascular remodeling leads to tissue hypoxia, which is followed by a depression in inner neuroretinal function. Here we examined whether genetic deletion of Cx43 or inhibition of its phosphorylation can reduce retinal hypoxia and restore neuronal responses to light stimuli.
WT, KO or KI mice were exposed to 75% oxygen from postnatal day (p) 7 to p12 and then returned to room air. At p17, the hypoxic retinal areas were examined with immunohistochemistry in retinal whole-mounts after intraperitoneal injection of Hypoxyprobe. At p28, the bipolar and amacrine cell functions were assessed with electroretinograms (ERG). The b-wave amplitudes and oscillatory potentials (OPs) elicited by stimuli of various light intensities were measured, and a generalized Naka Ruston equation was fit to the data to estimate the maximum response amplitude (Vmax), the slope and the semisaturation constant.
The hypoxic retinal regions of KO mice were significantly reduced compared to their control (WT) littermates by p17 (WT, 15.19 ± 1.49 vs KO, 7.607 ± 0.5467; n=6, p=0.0007). At p28, WT mice exposed to OIR showed reduced bipolar and amacrine cell scotopic responses measured with ERG. Deletion of astrocytic Cx43 partially, yet significantly, restored these responses, as demonstrated by enhanced rod-driven b-wave amplitudes (Vmax: WT, 172.4 ± 15.83 vs KO, 259.6 ± 25.75; n=5, p=0.02) and OPs. KI retinas also showed enhanced scotopic b-wave amplitudes compare to controls (Vmax: WT, 137.3 ± 21.46 vs KI, 245.9 ± 27.95; n=5, p=0.015).
Our results indicate that targeting Cx43 channels or their phosphorylation can restore vascular perfusion and neuroretinal function in ischemic retinopathies.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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