In oxygen-compromising conditions like diabetes, the body grows new blood vessels to help, but the result is often leaky, dysfunctional vessels that make bad matters worse.

Now scientists have identified a new target for reducing that dysfunctional blood vessel development in the eye in diabetic retinopathy.

“If we block the adenosine receptor A2a, the blood vessels will not leak and not as many new blood vessels will grow,” said Dr. Yuqing Huo, chief of the Vascular Inflammation Program at the Vascular Biology Center at the Medical College of Georgia at Augusta University.

An inhibitor of adenosine receptor A2a already is in clinical trials for Parkinson’s disease.

Adenosine is a natural structural component of basic body essentials like DNA and RNA as well as the ubiquitous cell fuel ATP. It can help blood vessels expand, battle bad heart rhythms and even provide pain relief. Its family of receptors includes adenosine receptor A2a, which is important for the retina and found on the endothelial cells that line blood vessels, said Huo, co-corresponding author of the study in the journal Nature Communications.

When oxygen levels are good, their expression is low in endothelial cells. But in diabetes, where oxygen levels go down, adenosine A2a receptor expression goes way up and a vicious cycle is born.

Endothelial cells that line the blood vessels of the retina begin to shrink, even disappear in diabetes. Expression of adenosine receptor A2a increases, apparently to enable endothelial cells to take up more glucose that can be converted to energy to help restore good oxygen and blood flow. In this case, that means repairing existing blood vessels and growing new ones in a process called angiogenesis. But in a scenario where the cells don’t use energy efficiently or build blood vessels well it’s actually called “pathological angiogenesis.” Old and new blood vessels alike readily bleed or contract, leading to hemorrhage and/or retinal detachment and blindness, the scientists write.

“They grow too much, too fast,” Huo said. It’s not yet clear whether it’s the high glucose levels of diabetes and/or the resulting inflammation or other factors that increase expression of adenosine receptor A2a. Huo notes that adenosine’s many actions include an anti-inflammatory effect.

But the work of Huo and his colleagues indicates that however it happens adenosine receptor A2a’s higher profile role in this scenario makes it a likely treatment target.

A key problem appears to be that the receptor aids the inefficiency of endothelial cells. These cells generate about 85 percent of their fuel through glycolysis, a way to convert glucose to the cell fuel ATP without using oxygen. Even with plenty of oxygen handy, endothelial cells appear to like this method. By comparison, cellular respiration, which requires oxygen, produces nearly 40 molecules of ATP per molecule of glucose versus only about two ATP molecules per glucose molecule with glycolysis.

When the scientists activate the receptor, it promotes the enzymes that promote glycolysis. Increased use of this inefficient energy production process of glycolysis has been shown to occur in endothelial cells in people with proliferative diabetic retinopathy.

Conversely, when the scientists knocked out or deleted adenosine receptor A2a from endothelial cells, it decreased glycolysis. Blocking glycolysis, in turn, dramatically inhibited blood vessel proliferation and sprouting of endothelial cells that overexpress the receptor.

When oxygen levels were more normal, knocking out or deleting adenosine receptor A2a didn’t seem to have that much impact on glycolysis, possibly because the receptor’s expression is not that high when oxygen levels are normal, the scientists suspect.

All the reciprocal cause and effect they found supports the new idea that the receptor promotes glycolysis, which pro