4.2.4. Angiogenesis

Increased iron levels in the retina could also have a role in the development of new vessels by inhibiting the anti-angiogenic effect of cleaved high molecular weight kininogen (Hka) [119], promoting the expression of succinate receptor 1 (SUCNR1 or GPR91) [120] which stimulates production of pro-angiogenic factors VEGF and angiopoietin [121]. *In Hjv*−/− mice, that leads to abnormal retinal iron overload. Proliferation of new leaky blood vessels in the vitreous was associated with reactive gliosis involving MGC and microglia [37]. In addition to proliferation by migratory cells, intravitreal hemoglobin also stimulates a transient proliferation in cells of the RPE and possibly in some supportive cells of the neural retina, such as MGC and astrocytes [122]. Iron also plays a role in HIF transcriptional regulation of pro-angiogenic genes [51]

### **5. Role of Iron in Retinal Diseases**

### *5.1. Siderosis and Retinal Hemorrhages*

Eye siderosis is probably the first known manifestation of iron toxicity for the eye. The presence of a foreign body containing iron inside the eyeball leads to various clinical complications including heterochromia of the iris, mydriasis, cataract, and retinal and RPE atrophy. Electroretinography analysis shows a decrease in a and b wave amplitudes, due to the progressive degeneration of the cones and rods (for a review, see [123]). The increase in iron can be observed histologically as a granular structure with FT or hemosiderin into cells. The level of vitreous iron also increases [124].

Retinal hemorrhages are present in several retinal pathologies, such as exudative AMD, diabetic retinopathy, or myopic degeneration, and they are particularly deleterious for vision when located in the subretinal space. Vision loss is dependent on the size of the hemorrhage and the ability of the tissue to shed blood [125,126]. During sub-macular hemorrhage early PR damage has been reported within 24 h [127]. In rabbits, the injection of their own blood into the subretinal space leads to a progressive degeneration of the PRs from one day after injection until a total destruction at 7 days, with an accumulation of iron in the outer segments of PR and in RPE [128]. The increased release of iron from hemoglobin induces peroxidation of unsaturated phospholipids, which are extensively present in the retina and a ffects particularly retinal neurons compared to the retinal glial cells [129].

### *5.2. Retinal Manifestations of Inherited Iron Disorders*

Iron can accumulate in the retina of patients with inherited diseases involving mutations in genes encoding proteins of iron homeostasis, which can cause an imbalance in the metabolism of retinal iron. The most common hereditary hemochromatosis is related to a mutation in the *Hfe* gene resulting in excessive absorption of iron by the intestine and its accumulation in the organs. Mutations in the *Tfr2*, *Fpn*, *Hjv*, and *Hepc* genes are also involved in the development of hemochromatosis. The clinical findings associated to the retinal iron accumulation in these patients, as well as the impact on visual function, are quite rarely reported due to the variability of penetrance and the existence of a treatment reducing systemic iron overload. However, iron deposits and other changes in the RPE as well as visual acuity loss have been already reported [130].

Aceruloplasminemia is an autosomal recessive disorder caused by mutations in the Cp gene, resulting in a defect in the export of iron from cells. The retina, brain, and pancreas are overloaded with iron, leading to the clinical consequences as retinal degeneration, dementia, and diabetes. Several cases associating yellow discoloration of the fundus, atrophy of the RPE, and drusen-like deposits in the macula have been described. In post-mortem sections, an accumulation of iron associated with an enlarged RPE and loss of pigment of the RPE was observed (for a review, see [27]).

In animal models invalidated for the genes coding for iron-related proteins, an accumulation of iron in the RPE and PR is systematically observed as well as abnormalities in the RPE and PR degeneration [25,35,39,52,131].

Studies carried out in aging rodents have shown that the increase in iron intakes in food or by intravenous injection leads to local iron deposits in the choroid, the RPE, and the segments of PR, as well as deposits of complement C3 in the Bruch's membrane, hypertrophy, and vacuolation of RPE and changes in the choriocapillaries [132,133].
