Nogo‐A inhibits vascular regeneration in ischemic retinopathy

Abstract

Nogo-A is a potent glial-derived inhibitor of axon growth in the injured CNS and acts as a negative regulator of developmental angiogenesis by inhibiting vascular endothelial cell migration. However, its function in pathological angiogenesis has never been studied after ischemic injury in the CNS. Using the mouse model of oxygen-induced retinopathy (OIR) which yields defined zones of retinal ischemia, our goal was to investigate the role of Nogo-A in vascular regeneration. We demonstrate a marked upregulation of the Nogo-A receptor sphingosine 1-phosphate receptor 2 in blood vessels following OIR, while Nogo-A is abundantly expressed in surrounding glial cells. Acute inhibition of Nogo-A with function-blocking antibody 11C7 significantly improved vascular regeneration and consequently prevented pathological pre-retinal angiogenesis. Ultimately, inhibition of Nogo-A led to restoration of retinal function as determined by electrophysiological response of retinal cells to light stimulation. Our data suggest that anti-Nogo-A antibody may protect neuronal cells from ischemic damage by accelerating blood vessel repair in the CNS. Targeting Nogo-A by immunotherapy may improve CNS perfusion after vascular injuries.

Nogo-A-targeting antibody promotes visual recovery and inhibits neuroinflammation after retinal injury

“…The involvement of Nogo-A in pathological mechanisms affecting the retina suggests that Nogo-A-targeting antibodies may also improve vision in ocular diseases. Our recent results revealed that blocking Nogo-A-Delta 20 with intravitreal injection of 11C7 antibody dramatically increased vascular repair and neuronal function in the retina of mice subjected to ischemic retinopathy 28 . In adult mice, we also reported that Nogo-A KO mice had better visual recovery after retinal injury than WT animals 29 .…”

“…A Ganzfeld system (Phoenix Research Labs, Pleasanton, CA, USA) was used to record photopic ERGs in mice (5-9/group) anesthetized with a ketamine/xylazine mixture, as described before 28,38 . Prior to recording, a drop of 1% Mydriacyl Tropicamide was applied on the cornea for pupil dilation.…”

“…The detection of Nogo-A-Delta 20 in the vitreous of injured eyes suggests that it may contribute to visual function loss after injury. This region of Nogo-A strongly inhibits neuronal repair/plasticity in the CNS 44 but can efficiently be neutralized in vivo using 11C7 antibody [26][27][28][29]45 . We therefore tested the function of Nogo-A-Delta 20 in NMDAinduced visual deficits by injecting 11C7 (2 μg/eye) or an equal amount of control IgG in the mouse vitreous ( Fig.…”

“…The optokinetic response was evaluated repeatedly before and after injury to monitor visual function variations 29,40 . Electroretinogram recordings allowed to follow retinal cell activity upstream of RGCs 28,38 . A quantitative analysis of surviving RGCs was carried out on retinal flat-mounts stained for RBPMS (Fig.…”

“…In adult mice, we also reported that Nogo-A KO mice had better visual recovery after retinal injury than WT animals 29 . Here, we hypothesized that retinal Nogo-A may inhibit injured neuron repair 28,[30][31][32][33] . Indeed, immunofluorescent observations revealed high levels of Nogo-A in radial Müller glia, a specialized retinal glia, and to a lower extent in RGCs.…”