Vascular Cell Biology

The long-term complications of diabetes include problems as varied as eye, kidney, heart and nerve damage, with most of the major pathologies involving the blood vessels. Researchers in the Section on Vascular Cell Biology have made significant contributions to the understanding of the molecular and genetic changes that take place in blood vessels and cause diabetic complications.
    
Investigators in the section pioneered a research model that is now in use around the world. Challenged by a lack of donated heart, kidney and eye tissue to study, investigators created cell cultures to determine how elevated glucose and insulin resistance cause abnormalities in these tissues—essentially creating models of diabetic complications in a petri dish. Although researchers elsewhere have used cell cultures to study genetic diseases, the model developed at Joslin was one of the first to use cell cultures for the studies of glucose metabolism in chronic diseases involving blood vessels. This groundbreaking approach helped researchers in the section to develop new theories about how diabetic complications begin, and to design and test interventions in animals and in people.
 
A dramatic example of this approach is a discovery that led to a new drug, which is now undergoing a priority review by the U.S. Food and Drug Administration (FDA) for use in treating diabetic eye disease. In a series of studies, researchers in the section found that elevated levels of blood glucose indirectly activate protein kinase C (PKC), which when activated improperly can cause blood vessel dysfunction and pathologies. Over the last 10  years, researchers in the section designed a PKC inhibitor to prevent, or at least slow, blood vessel damage and the resulting diabetic complications. Thus far the FDA has deemed the drug “Approvable” for this indication pending additional study data.

Several investigations currently under way in the section are providing insights into why insulin resistance and diabetes increase the risk of cardiovascular disease. One group of investigators, for instance, has proposed a new theory that elevated glucose and insulin resistance may inhibit certain proteins that belong to the PI 3-kinase and Akt signaling pathways, thereby contributing to atherosclerosis (the buildup of fatty deposits in blood vessels) and heart disease. In addition, these researchers have suggested that the loss of this type of insulin’s actions could be responsible for deceased levels of vascular endothelial growth factor (VEGF), a growth factor for blood vessel in the heart and legs which can be causing the increases in heart attacks and poor wound healing in people with diabetes. The theory, now being studied in animals, may yield new targets for drugs to prevent atherosclerosis.
 
Other investigators in the section have helped explain why angiotensin-converting enzyme (ACE) inhibitors (common heart medications) slow the development of vascular disease in people with diabetes. Angiotensin is a hormone best known as a contributor to high blood pressure and kidney disease; studies indicate it also may contribute to eye and heart complications in people with diabetes.  Researchers in the section have discovered how angiotensin regulates genes and proteins in the walls of blood vessels, causing a cascade of damage. One recent discovery revealed that angiotensin regulates the PAI-1 gene, which is overactive in the blood vessels of people with type 2 diabetes and promotes atherosclerosis. These studies may help identify further drug targets to prevent heart and vascular disease.

Other investigators in the section are discovering ways to prevent oxidative stress, which contributes to diabetic complications such as blood vessel damage and kidney disease. Oxidative stress results when a toxic form of oxygen builds up in tissues.
 
One set of investigations showed that diabetes reduces the activity of a critical enzyme, G6PD, which produces a major antioxidant known as NADPH. As NADPH levels decrease, oxidative stress occurs.  NADPH is also important for many other cellular processes including the production of nitric oxide, which increases blood vessel size and lowers blood pressure. A set of studies has shown that decreased NADPH leads to decreased nitric oxide and might contribute to high blood pressure. Researchers in the section also have conducted clinical trials that showed that high doses of the antioxidant vitamin E could help prevent damage to small blood vessels in the eyes and kidneys. Studies are now under way to find other agents that might help protect against oxidative stress and thus prevent long-term complications from developing or getting worse.