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 Statement
S. Pran Babu and T. W. Corson are named inventors on patent applications related to this work.
Abbreviations
- BSA
- bovine serum albumin
- DAI
- days after injection
- DMSO
- dimethyl sulfoxide
- EdU
- 5-ethynyl-2′-deoxyuridine (EdU)
- ERG
- electroretinogram
- eNOS
- endothelial nitric oxide synthase
- EPP
- erythropoietic protoporphyria
- ETC
- electron transport chain
- FA
- fluorescein angiography
- FECH
- ferrochelatase
- GCL
- ganglion cell layer
- GFAP
- glial fibrillary acidic protein
- GS-IB4
- Griffonia simplicifolia isolectin B4
- H&E
- hematoxylin and eosin
- HIF-1
- hypoxia inducible factor 1
- HO-1
- heme oxygenase 1
- INL
- inner nuclear layer
- NMPP
- N-methyl protoporphyrin
- OCT
- optical coherence tomography
- OIR
- oxygen induced retinopathy
- ONL
- outer nuclear layer
- PBS
- phosphate buffered saline
- PDR
- proliferative diabetic retinopathy
- PFA
- paraformaldehyde
- PPIX
- protoporphyrin IX
- ROP
- retinopathy of prematurity
- VEGF
- vascular endothelial growth factor