The soluble epoxide hydrolase attenuates pathological vascularization by preventing astrocyte loss in a retinopathy of prematurity model in mice

Abstract

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. Several signalling pathways have been implicated in the process of ROP but a novel drugable target is the cytochrome P450 (CYP)/soluble epoxide hydrolase (sEH) pathway. The latter enzymes play a crucial role in biological processes by generating bioactive epoxides and diols from endogenous polyunsaturated fatty acids (PUFAs). This study aimed to characterize the effects of the newly identified sEH‐derived w‐3 PUFA diol; 19,20‐dihydroxydocosapentaenoic acid (DHDP) in a mouse ROP model.ROP in mice was achieved by placing pups in 75% oxygen for 5 days from postnatal day (P) 7 until P12, before moving animals back to room air for an additional 5 days. This procedure resulted in the development of avascular areas that were significantly larger in retinas from sEH−/− mice than in their wild‐type (WT) littermates at P17. Avascularization was accompanied by angiogenesis in the form of characteristic vascular “tufts” which were more evident in retinas from sEH−/− mice. Although there was no difference in vascular obliteration, a marked decrease in the astrocyte network was observed in sEH−/− mice after exposure to high oxygen. Mechanistically, astrocyte loss in hyperoxic conditions was a consequence of elevated mitochondrial (mt) DNA damage mediated by increased interaction of the PARP‐1 DNA binding domain with mtDNA, as revealed by chromatin immunoprecipitation studies. Exposure of astrocytes to 75% O2 in vitro resulted in elevated PARP‐1 cleavage/activation; a phenomenon reversed in the presence of 19,20‐DHDP. Administration of 19,20‐DHDP during hyperoxia preserved the complex of presenilin 1 with mitochondrial carrier homolog 1 (MTCH‐1) in the outer mitochondria membrane, inhibiting the translocation of the MTCH‐1 to the inner mitochondria membrane and subsequently inhibiting PARP‐1 cleavage. The intravitreal injection of 19,20‐DHDP at day 7 significantly prevented astrocyte loss caused by high O2 levels at day 8, and reduced both the avascular area as well as vascular tuft formation at P17 in the sEH−/− mice.Our date indicate that the sEH dependent generation of 19,20‐DHDP from w‐3PUFA is required for retinal astrocyte survival and preservation of DNA integrity under hyperoxic conditions.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.