Cytochrome P450 monooxygenase lipid metabolites regulate choroidal neovascularization in the eye: contribution of the soluble epoxide hydrolase.

Abstract

Purpose : Age-related macular degeneration (AMD) is the most common cause of blindness for the elderly in the developed world. Abnormal growth of choroidal blood vessels, or choroidal neovascularization (CNV), is a hallmark of the neovascular (wet) form of advanced AMD and leads to significant vision loss. A growing body of evidence supports a strong link between neovascular disease and inflammation. Metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) derived from the cytochrome P450 (CYP) monooxygenase pathway serve as vital second messengers that regulate a number of hormones and growth factors involved in inflammation and vascular function.

Methods : The present study adheres to ARVO’s Statement for the Use of Animals in Ophthalmic and Vision Research. Utilizing a mouse model of CNV, we characterized the role of these lipid metabolites in regulating neovascular disease.

Results : We discovered that the CYP-derived lipid metabolites epoxydocosapentaenoic acids (EDPs) and epoxyeicosatetraenoic acids (EEQs) are vital in dampening CNV severity. Specifically, overexpression of epoxygenase CYP2C8 or genetic ablation/inhibition of the soluble epoxide hydrolase (sEH) enzyme led to increased levels of EDP and EEQ with attenuated CNV development. In contrast, when we promoted the degradation of these CYP-derived metabolites by transgenic overexpression of sEH, the protective effect against CNV was lost. We found that these molecules work in part through their ability to regulate the expression of key leukocyte adhesion molecules, on both leukocytes and endothelial cells, thereby mediating leukocyte recruitment.

Conclusions : These results suggest that CYP-derived lipid signaling molecules and their regulators are potential therapeutic targets in neovascular diseases. Inhibition of sEH prolonged the bioavailability of these potent bioactive lipids and conferred increased protection in the laser-induced CNV model.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.