Finding New Targets to Treat Vascular Damage

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Dr. Rask-Madsen in his lab

Diabetes increases the risk of damage to blood vessels all throughout the body. It also impairs the body’s ability to grow new blood vessels, a process called angiogenesis. Right now, there are no medications to improve angiogenesis, because the exact mechanisms of how diabetes causes damage still remain mysterious. But researchers from Joslin Diabetes Center discovered a gene that could become a drug target to help stimulate angiogenesis.

This recently published research was inspired by a study done by cancer researchers. Those researchers genetically engineered mice so that a family of genes known to suppress tumor formation never got turned on. They noticed that when these genes were turned off, the mice grew new blood vessels.

These tumor suppressing genes controlled the actions of 21 different genes that reside in the linings of blood vessels. This triggered in the Joslin researchers the idea that these genes could start a diabetes-related chain reaction that affected the growth of new blood vessels. The research was done in the lab of Christian Rask-Madsen, M.D., Ph.D., Assistant Investigator in the Section of Vascular Cell Biology at Joslin and Assistant Professor at Harvard Medical School.

The researchers followed the path that started with the actions of the tumor suppressing genes. They eventually discovered that there was an overlap between one of the members of this gene family and insulin: they both played a role in the actions of 10 genes found in the blood vessel linings. They tested each of these 10 genes in turn until they landed on a likely candidate for why angiogenesis increased when the tumor-suppressing genes were turned off, a gene called CITED2.

This means that when the tumor-suppressing gene family is turned off, there isn’t very much CITED2 in the cell. The researchers knew from previous studies that high levels of CITED2 interfered with the action of a gene known as HIF, which helps to activate the formation of blood vessels (angiogenesis). This chain reaction was the reason the cancer researchers noticed an increase in angiogenesis when they turned off those tumor-suppressing genes.

Levels of CITED2 can also be reduced by the presence of insulin on the cell surface. Insulin resistance prevents the right amount of insulin from getting to the cells. Through a series of experiments, the researchers confirmed that in people with type 2 diabetes  that have significant insulin resistance, levels of CITED2 are high and they prevent the HIF gene from helping along the formation of new blood vessels.

Knowing the role CITED2 plays in hindering angiogenesis could make it a target for new medications that would reduce the activity of the gene in cells.

“CITED2 acts as a brake on HIF activity, and that brake is increased in diabetes and obesity, where you have increased CITED2,” Dr. Rask-Madsen says. “These results advance our understanding of insulin action on vascular cells, and they point to potential new therapeutic approaches to improve angiogenesis in patients with type 2 diabetes and obesity.”

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