Retinopathy of prematurity (ROP) is the major cause of serious visual impairment in childhood. ROP is characterised by a phase of arrest in vascular development associated with retinal vaso-obliteration and an ensuing aberrant preretinal vasoproliferative phase. The relative postnatal hyperoxia clearly plays a dominant role in the genesis of ROP. The retina of premature infants is devoid of sufficient antioxidants. Accordingly, upon exposure to hyperoxia peroxidation propagates. Antioxidants are only marginally effective to prevent ROP and may be toxic. We proposed that products of peroxidation may exert cytotoxicity to retinal endothelium and consequently represent better targets of disease. We identified numerous products of peroxidation that partake in retinal vaso-obliteration, such as isoprostanes, neuroprostanes and transarachidonic acids. These factors result in an undervascularised and hence ischaemic retina. Activation of hypoxia inducible factor/vascular endothelial growth factor (VEGF) has been amply documented. However, early injury to the endothelium triggers the activation of proliferative factors. Along these lines, we demonstrated that the coagulation factor VIIa, which activates proteinase-activated receptor type 2, leads to endothelial cell proliferation by inducing expression of the pro-angiogenic factor Tie2. However, because the mitochondria is a major oxygen sensing organelle, we postulated that Krebs cycle products accumulate during the ischaemic phase and partake in the endothelial cell proliferation. Our findings uncover a novel role for succinate acting via the GPR91 receptor, to elicit robust retinal neovascularisation; succinate/GPR91 evoke properties of a master regulator of numerous angiogenic factors (VEGF, angiopoietins 1 and 2, suppression of thrombospondin 1). Overall, our observations have uncovered major mediators implicated in the genesis of ROP.
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