Researchers from the University of São Paulo (USP) are helping to discover alterations in the functioning of retina cells that lead to an increased proportion of premature babies, which could surpass 30% in some regions and countries, having eyesight problems. Located in the back part of the eye, the retina is the structure responsible for capturing light and converting it into electrical signals, which, upon reaching the brain, create images. It only begins to mature in the final weeks of pregnancy. When a child is born before the 32nd week of pregnancy or with a weight of less than 1.5 kilos and needs to receive Intensive Care Unit (ICU) treatment, such as oxygen supplementation, the retina does not mature well. With the withdrawal of oxygen, the blood vessels that feed it sometimes begin to proliferate in an exaggerated manner, which can leave scars at the back of the eye and lead to a loss of vision. Known by the name of retinopathy of prematurity, it is one of the main causes of blindness in childhood — it is what led the US musician and singer Stevie Wonder to not be able to see.
Using mice and reproducing similar conditions to those of newborn children that spent a period in ICU, biochemists Ricardo Giordano and Sayuri Miyamoto, both from the Institute of Chemistry (IQ) at USP, and their collaborators have now identified alterations in the availability of lipids (fats) in the retina and in its use of these compounds. The results, published in June in the journal iScience, help to understand why the cells of this structure of the eye can stop working properly.
As vessel proliferation advanced in the experiment with the rodents, biochemists Alex Inague and Lilian Alecrim, who are doing PhDs under the guidance of Miyamoto and Giordano, respectively, observed an important change in the quantities of 277 (92%) of the 300 types of lipids naturally found in the cells of the retina. Lipids are organic molecules made by long sequences of carbon (C) atoms, to which hydrogen (H), oxygen (O), nitrogen (N), and phosphorous (P) atoms are attached. They are composed of different types of oils and fats and perform essential roles in the body. They are the main components of the membrane, the surrounding fluid that separates the cell organelles from the external environment and controls the entry of compounds into the cells, as well as functioning as a source of energy. They also act as chemical messengers, sending information to both the interior of the cell as well as other tissues.
In the retina, the availability of lipids and their proper functioning in chemical reactions are even more important. Its cells, just like those of the heart and other muscles, have high energy consumption. To remain active, they consume both the energy available in the glucose molecules as well as that stored by certain lipids. Additionally, these cells suffer more accelerated degradation from interacting with light and oxygen molecules and need to substitute the damaged lipids to remain intact and survive. It is estimated that, every day, the light receptor cells (known as photoreceptors) replace up to 10% of the lipids from the outer layer of its membrane.
Inague and Alecrim measured the lipid concentrations at different stages of the retinopathy and observed three main phenomena. The first was an increased quantity in the diseased retina of neutral lipids, nonpolar molecules that, in general, function as an energy reserve — their levels were at least three times higher than those found in healthy tissue. In retinopathy, the neutral lipids also appear to group in the interior of the cells and form droplets, inside which lipids more sensitive to the action of the oxygen molecules were found. Both the increase in the level of these lipids as well as in the formation of droplets was confirmed by greater expression of genes that encode proteins associated to the synthesis of these compounds and the organization of these fat vesicles in the cells. In a study published in 2015 in the journal Cell, the team of Alex Gould, of the Francis Crick Institute, in the UK, verified that by housing the most flexible fatty acids of the membrane, these droplets protect us from the damaging action of the oxygen molecules. “It is as if, in the illness, the cell tried to protect its most noble material,” says Inague.
The third phenomenon was an important reduction in the availability of omega-3- and omega-6-type fatty acids, accompanied by a significant increase in omega-9 fatty acids. The reduction was expected, since birth cuts the supply that would previously reach the baby via the placenta. For this reason, doctors sometimes give nutritional supplementation containing omega-3 and omega-6 to try to prevent damage to the retina. The results are not always satisfactory. “Apparently there is an alteration in the metabolism that the supplementation does not supply. Maybe that’s why it is not completely effective,” explains Miyamoto.
“Studies like this are important because they shine light on the mechanisms involved in the development of the disease,” says ophthalmologist Eliane Chaves Jorge, of the School of Medicine at São Paulo State University (UNESP), a specialist in retinopathy of prematurity. “The results show that lipid remodeling [alteration in the concentration, availability, and use of these molecules] occurs in retinopathy, which could explain why supplementation with omega-3 and omega-6 does not always have the expected effect,” explains the physician.
In 2019, Giordano’s team had already analyzed how the activity of genes in cells of the retina of rodents with retinopathy of prematurity evolved. At the time, the researchers identified an increase in the activation of around 3,000 genes, the majority associated to the formation of new blood vessels (angiogenesis). “In the first study, we looked at the gene expression, but we noticed that it did not allow us to explain everything that happened with the retina cells in this illness. That’s why we then studied the lipids. Now we are analyzing what happens with the proteins,” says Giordano. “We want to understand everything that is happening.”
1. Molecular mechanisms of angiogenesis and vascular heterogeneity (nº 19/25828-8); Grant Mechanism Thematic Project; Principal Investigator Ricardo Jose Giordano (IQ-USP); Investment R$1,768,922.73.
2. Redoxoma (nº 13/07937-8); Grant Mechanism Research, Innovation, and Dissemination Centers (RIDC); Principal Investigator Ohara Augusto (IQ-USP); Investment R$62,754,313.69.
3. Mechanisms of oxidized biological membrane detoxification and repair involving the action of the peroxiredoxin 6 enzyme (nº 17/13804-1); Grant Mechanism Direct Doctoral (PhD) Fellowship; Supervisor Sayuri Miyamoto (IQ-USP); Beneficiary Alex Inague; Investment R$235,935.57.
INAGUE, A. et al.Oxygen-induced pathological angiogenesis promotes intense lipid synthesis and remodeling in the retina. iScience. vol. 26, no. 6. june 16, 2023.