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Sandrine Joly, Agnieszka Dejda, Lea Rodriguez, Mike Sapieha, Vincent Pernet; The inhibition of Nogo-A promotes vascular and neuronal recovery in a mouse model of proliferative retinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3583.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously observed that the glial-derived protein Nogo-A inhibited vascular endothelial cell growth in vitro and in vivo. Whether Nogo-A contributes to pathological angiogenesis in the retina is not known. Our aim was thus to address the potential implication of Nogo-A in blood vessel remodeling in proliferative retinopathy.
The classical model of oxygen-induced retinopathy (OIR) was used in C57BL/6J mice to study blood vessel degeneration and aberrant neovascularization. The expression of Nogo-A and its receptors was monitored by Western Blotting, qRT-PCR and immunofluorescence on retinal histological sections. In blocking experiments, Nogo-A was acutely neutralized by injecting 11C7 antibody (1 mg) in the vitreous of postnatal day 12 (P12) mice. Control mice received anti-BrdU antibody (αBrdU). Vaso-obliteration and neovascularization were examined on retinal flat-mounts at P17. Electroretinogram (ERG) recordings and histological analyses were carried out in OIR adult mice to follow the functional and structural changes induced by 11C7 and αBrdU treatments.
Our results revealed a strong upregulation in sphingosine 1-phosphate receptor 2 (S1PR2), a Nogo-A receptor, in the blood vessels of OIR mice, while Nogo-A was highly expressed in surrounding Müller glia. Nogo-A could not be detected in astrocytes and microglia. 11C7 injection dramatically increased blood vessel regeneration and reduced pathological neovascularization towards the vitreous. In addition, the number of filopodia was increased in tip cells after the administration of 11C7. With 11C7, ectopic tip cells could be observed growing into the outer nuclear layer of photoreceptors at P17 mice but not at P60. ERG responses showed that 11C7 protected the retinal function in adult mice; ERG a-wave and b-wave amplitudes were doubled in 11C7-treated eyes compared with control animals administered with αBrdU. On histological sections, the inner retinal layer thickness was better preserved with 11C7 than after αBrdU delivery. Interestingly, the expression of VEGF and P-VEGFR2 was not affected by 11C7 treatment in retinal lysates.
Our data show that neutralizing Nogo-A allows to protect retinal cells from ischemic damage by stimulating blood vessel regeneration in a model of proliferative retinopathy. Nogo-A may thus be used as a new therapeutic target to treat diabetic retinopathy.
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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