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Dolly Ann Padovani-Claudio, Samuel A Palmer, Nolan J. Beatty, John S Penn; Chemokine modulation as a potential therapy for retinal angiogenesis.. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2721. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
CXCL8 is an angiogenic chemokine known to accumulate in the vitreous of patients with retinal neovascularization, and its mouse homologues are upregulated in the experimental model of oxygen-induced retinopathy (OIR) coincident with pre-retinal neovascularization. However, we do not fully understand the functional implications of CXCL8’s accumulation in the retina. We tested the hypothesis that exogenous vitreous CXCL8 would accelerate radial retinal vascular growth in mice developing in normoxic conditions, and that genetic manipulation of CXCR2, the receptor for the mouse CXCL8 homologues, would decrease pathologic pre-retinal neovascularization in OIR.
To evaluate developmental retinal vascularization, we injected either CXCL8 or 0.1%BSA in contralateral eyes of P4 wild-type c57BL/6J mice and sacrificed at P8. To evaluate the effect of blocking CXCL8 signaling in OIR, mixed genotype P7 pups from heterozygous Cxcr2+/- c57BL/6J breeding pairs were exposed to 75% oxygen until P12, then returned to room air and sacrificed at P18. Enucleated eyes were fixed in 4% paraformaldehyde and retinas were dissected and stained with isolectin-B4. A masked observer traced images of fluorescently labeled flat-mounted retinas to quantify: vascular radial growth and retinal radial span in P8 eyes, or avascular, neovascular, and total retinal areas from P18 eyes. Data was pooled from several experiments and assessed for significance using a two-tailed t-test.
Exogenous vitreous CXCL8 accelerates radial retinal vascular growth between P4 and P8 by at least 5% (P=0.053), reducing retinal avascularity by 33% compared to vehicle (N=5 eyes/group). In OIR, Cxcr2-/- mutation reduced neovascular area by ~30% (P<0.0001) when compared to Cxcr2+/+ (wild-type) littermate controls (N=12 eyes/group) while the percent avascular retina was not significantly different between them.
Vitreous CXCL8 and VEGF levels correlate with neovascularization in angiogenic retinopathies such as diabetic retinopathy and retinopathy of prematurity. VEGF is the mainstay target of drug therapies for these conditions and few alternative therapies have been developed. Our findings support the notion that targeting the CXCL8/CXCR2 signaling pathway may provide a novel approach to treat these conditions reducing pre-retinal neovascularization without a significant alteration in physiologic vascular growth.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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