The role of cytochrome P450 epoxygenases in retinal angiogenesis.

Capozzi ME, McCollum GW, Penn JS
Invest Ophthalmol Vis Sci. 2014 55 (7): 4253-60

PMID: 24917142 · PMCID: PMC4098062 · DOI:10.1167/iovs.14-14216

PURPOSE - The purpose of this study was to investigate the role(s) of cytochrome P450 epoxygenases (CYPs) and their products, the epoxyeicosatrienoic acids (EETs), in hypoxia-induced VEGF production and pathologic retinal angiogenesis.

METHODS - Human retinal astrocytes, Müller cells, and retinal microvascular endothelial cells (HRMEC) were exposed to hypoxia, and relative CYP2C expression was measured by RT-PCR. Astrocyte and Müller cell VEGF production was measured by ELISA after exposure to hypoxia and treatment with the general CYP inhibitor, SKF-525a. Human retinal microvascular endothelial cells were treated with the CYP product, 11,12-epoxyeicosatrienoic acid [EET], or SKF-525a in the presence or absence of VEGF. Proliferation of HRMEC and tube formation were assayed. Oxygen-induced retinopathy (OIR) was induced in newborn rats. Retinal CYP2C11 and CYP2C23 expression were measured by RT-PCR. The OIR rats received SKF-525a by intravitreal injection and preretinal neovascularization (NV) was quantified. Retinal VEGF protein levels were measured by ELISA.

RESULTS - Human retinal astrocytes were the only cells to exhibit significant induction of CYP2C8 and CYP2C9 mRNA expression by hypoxia. Astrocytes, but not Müller cells, exhibited reduced hypoxia-induced VEGF production when treated with SKF-525a. 11,12-EET induced HRMEC proliferation and tube formation, and SKF-525a inhibited VEGF-induced proliferation. Oxygen-induced retinopathy induced expression of CYP2C23, but had no effect on CYP2C11. SKF-525a inhibited retinal NV and reduced retinal VEGF levels in OIR rats.

CONCLUSIONS - The CYP-derived 11,12-EET may exhibit a proangiogenic biological function in the retina following stimulation by hypoxia in astrocytes. Inhibition of CYP may provide a rational therapy against retinal NV, because it can reduce VEGF production and VEGF-induced angiogenic responses in endothelial cells.

Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

MeSH Terms (23)

Animals Animals, Newborn Aryl Hydrocarbon Hydroxylases Astrocytes Cell Proliferation Cells, Cultured Cytochrome P-450 CYP2C8 Cytochrome P-450 CYP2C9 Cytochrome P-450 Enzyme System Disease Models, Animal Endothelium, Vascular Enzyme-Linked Immunosorbent Assay Female Gene Expression Regulation, Developmental Humans Microcirculation Rats Rats, Sprague-Dawley Real-Time Polymerase Chain Reaction Retina Retinal Neovascularization RNA, Messenger Vascular Endothelial Growth Factor A

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