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 Fech^m1Pas 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.

中文翻译：

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亚铁螯合酶调节视网膜新血管形成

铁螯合酶（FECH）是血红素生物合成中的末端酶。我们以前表明，FECH是体外内皮细胞生长和体内脉络膜新血管形成所必需的。但是，尚未在视网膜新血管形成中探索FECH，视网膜新血管形成是增生性糖尿病性视网膜病和早产儿视网膜病等疾病的基础。在这里，我们研究了在氧气诱导的视网膜病变（OIR）小鼠模型中使用遗传和化学方法对FECH的抑制作用。在OIR小鼠中，FECH表达上调并与新生血管簇共定位。部分功能丧失的Fech ^m1Pas突变小鼠在OIR中显示视网膜新生血管减少和内皮细胞增殖减少。玻璃体内注射FECH抑制剂N-甲基原卟啉具有类似的作用。灰黄霉素是一种抗真菌药物，可抑制FECH（脱靶作用）。引人注目的是，玻璃体内灰麻黄素比媒介物更快地阻止了病理簇簇的形成和血管渗血的血运重建区域，表明其可能是靶向FECH的疗法。眼毒性研究表明，成年小鼠玻璃体内注射灰黄霉素不会破坏视网膜的脉管系统，功能或形态。总而言之，Fech的突变和化学抑制作用可减少视网膜新血管形成并促进生理性血管生成，提示在FECH抑制后对血管修复具有双重作用，而没有眼毒性。这些发现表明FECH抑制剂可用于治疗视网膜新血管形成。