To our knowledge, this is the first demonstration that CYP inhibition can reduce neovascularization in an in vivo model of retinopathy. It recently has been shown that retinal
Cyp2c expression is increased in mice exposed to hyperoxia.
41 In addition, human
CYP2C8 overexpression in OIR-exposed mice fed ω-3-enriched diet promoted retinal angiogenesis.
41 Similarly, we showed an upregulation of
CYP2C23 expression in rats during the post-oxygen exposure period in OIR rats. Moreover, we showed that inhibition of CYP activity, and presumably the consequent decrease in EET levels, reduces retinal NV. In rat OIR, retinal VEGF normally peaks at 14(2).
27 In this study, OIR rats receiving intravitreal injections of SKF-525a showed reduced retinal VEGF levels at 14(2) (
Fig. 7), perhaps contributing to the inhibition of retinal NV we observed at 14(6). Induction or exogenous addition of EETs has been shown to induce VEGF.
42 Inhibition of CYP2C9 by sulfaphenazole suppressed the hypoxia-induced transcriptional activity of the VEGF hypoxia response element in human umbilical arterial endothelial cells.
43 In human dermal microvascular endothelial cells, 14,15-EET induced VEGF via a Src-STAT-3-dependent mechanism.
42 However, in the retina, endothelial cells are not the major source of hypoxia-induced VEGF; Müller cells and astrocytes are the primary producers of VEGF of the retinal cell types.
5 We found that inhibition of CYP epoxygenases in hypoxia-induced primary human Müller cells had no effect on VEGF production; however, it significantly reduced production of VEGF by astrocytes (
Fig. 3). This suggests that astrocytes are the primary cell type involved in SKF-525a inhibition of retinal VEGF.