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Good for One, Bad for Another

Posted by Ilena Di Toro | Posted on January 5, 2021

Vascular Endothelial Growth Factor (VEGF) is a protein that our bodies produce to promote the growth of new blood vessels. This is a good thing since more blood vessels mean more oxygen goes to the tissues. The lungs have VEGF because blood flow is so important.

Of course, what’s good for one organ isn’t good for another organ. While VEGF is good for the lungs, it is bad for the eyes. Sometimes cells in the eye can produce too much VEGF and that leads to more blood vessels in the eye. Having too many blood vessels is a sign of retinal diseases such as age-related macular degeneration or diabetic retinopathy. While there are anti-VEGF drugs that block the growth of this protein and subsequently slows down the growth of blood vessels, these drugs just stabilize conditions. They aren’t a cure, they don’t work for everyone and there are safety issues.

Are there other ways to prevent excess blood vessels from forming in the eye that don’t have the side effects that anti-VEGF drugs do? Wouldn’t you know it, research is currently taking place at Scripps Research, in California, to learn more about this. Scientists there have found that not directly targeting the VEGF protein worked in mice and works better than anti-VEGF drugs.

The increase in blood vessels in the eye is the body’s attempt, albeit a faulty one, to reestablish blood supply that was damaged by aging, high cholesterol in the blood, diabetes or other factors. The decrease in oxygen, also known as is hypoxia sensed by another protein called HIF-1α, which leads to boosting the VEGF. While that sounds good, it can lead to abnormal and leaky blood vessels. While anti-VEGF drugs can stabilize this response and even improve vision, it doesn’t work for 40 percent of those who are given the drugs. Also, blocking VEGF can harm healthy tissue in the retina.

Martin Friedlander, MD, PhD, professor in the Department of Molecular Medicine at Scripps Research and Rebecca Berlow, PhD, were co-authors of this study. For a 2017 paper published in Nature they described another protein that decreases the hypoxic response. The protein is CITED2 and it is produced by HIF-1α as part of the hypoxic response. CITED2 is a regulator that blocks HIF-1α ability to turn on the hypoxic response genes. This keeps the response from being too strong or staying on too long.

For a new study, they tested a mouse model of hypoxia by using a part of the CITED2 that has the hypoxic response blocking elements. When a solution of the CITED2 was injected into the eye, it lessened the activity of the genes that are switched on by the HIF-1α protein in the cells of the retina. This reduces the growth of new blood vessels that are responsible for progressive vision loss. This also both preserved healthy blood vessels and allowed them to grow in the retina.

Using the same mouse model, scientists tested an anti-VEGF drug called aflibercept. While this drug reduced the excessive growth of blood vessels, it didn’t prevent the destruction of blood vessels in the retina. When aflibercept was combined with the CITED2 fragment, it reduced both the excessive growth of blood vessels and preserved and restored blood vessels in the retina.These results demonstrated CITED2’s capacity to combine these two benefits and the hope is to develop CITED2 based treatments with the goal of testing it in human trials.

Like many things, our cells respond to tweaking and if you tweak it right, you get a good outcome.


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