Ferrochelatase regulates retinal neovascularization

Abstract

Ferrochelatase (FECH) is the terminal enzyme in heme biosynthesis. We previously showed that FECH is required for endothelial cell growth in vitro and choroidal neovascularization in vivo. But FECH has not been explored in retinal neovascularization, which underlies diseases like proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the inhibition of FECH using genetic and chemical approaches in the oxygen-induced retinopathy (OIR) mouse model. In OIR mice, FECH expression is upregulated and co-localized with neovascular tufts. Partial loss-of-function Fechm1Pas mutant mice showed reduced retinal neovascularization and endothelial cell proliferation in OIR. An intravitreal injection of the FECH inhibitor N-methyl protoporphyrin had similar effects. Griseofulvin is an anti-fungal drug that inhibits FECH as an off-target effect. Strikingly, intravitreal griseofulvin blocked pathological tuft formation and revascularized areas of vasoobliteration faster than vehicle, suggesting potential as a FECH-targeting therapy. Ocular toxicity studies revealed that intravitreal injection of griseofulvin in adult mice does not disrupt retinal vasculature, function, or morphology. In sum, mutation and chemical inhibition of Fech reduces retinal neovascularization and promotes physiological angiogenesis, suggesting a dual effect on vascular repair upon FECH inhibition, without ocular toxicity. These findings suggest that FECH inhibitors could be repurposed to treat retinal neovascularization.Competing Interest StatementS. Pran Babu and T. W. Corson are named inventors on patent applications related to this work.AbbreviationsBSAbovine serum albuminDAIdays after injectionDMSOdimethyl sulfoxideEdU5-ethynyl-2′-deoxyuridine (EdU)ERGelectroretinogrameNOSendothelial nitric oxide synthaseEPPerythropoietic protoporphyriaETCelectron transport chainFAfluorescein angiographyFECHferrochelataseGCLganglion cell layerGFAPglial fibrillary acidic proteinGS-IB4Griffonia simplicifolia isolectin B4H&Ehematoxylin and eosinHIF-1hypoxia inducible factor 1HO-1heme oxygenase 1INLinner nuclear layerNMPPN-methyl protoporphyrinOCToptical coherence tomographyOIRoxygen induced retinopathyONLouter nuclear layerPBSphosphate buffered salinePDRproliferative diabetic retinopathyPFAparaformaldehydePPIXprotoporphyrin IXROPretinopathy of prematurityVEGFvascular endothelial growth factorView Full Text