Vascular Cell Biology
Determining How Complications Begin
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.
The Section on Vascular Cell Biology also includes Joslin's world-leading science in diabetes eye complications. Diabetes is the leading cause of blindness in people ages 20 to 74 in the United States. To determine how diabetic eye disease develops and to find strategies to preserve vision, researchers conduct molecular, biochemical, cellular and clinical studies.
Roots of Cardiovascular Disease
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 have discovered how angiotensin regulates genes and proteins in the walls of blood vessels, causing a cascade of damage. These studies may help identify further drug targets to prevent heart and vascular disease.
Preventing Oxidative StressOther 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.
Investigating Vascular Changes in the Eye
Diabetic retinopathy (eye disease) results in visual loss though two main mechanisms. In one condition, diabetic macular edema (DME), the small blood vessels of the retina leak fluid into the macula in the center of the retina, impairing vision. In the other condition, proliferative diabetic retinopathy (PDR), blood vessels in the retina grow where they should not.
Researchers in the section conduct studies to understand the basic molecular mechanisms underlying retinal vascular disease—in particular, the activity of growth factors in PDR and DME—and use results to design animal and clinical trials. In pioneering work, researchers defined the role of vascular endothelial growth factor (VEGF), hepatocyte growth factor, pigment epithelial-derived factor and others, and tested novel inhibitors of these pathways in cells, animals and humans. In addition, they identified new areas on the genes that control the expression of these molecules.
Novel Eye Imaging Techniques
The section is internationally recognized for its expertise in novel imaging methods. The eye is unique in that its vasculature, microvasculature and neuronal systems can be visualized directly in vivo, enabling noninvasive evaluation of biological processes. For example, a retinal imaging system called the Joslin Vision Network (JVN) uses a combination of video cameras and computers to image the back of the eye without dilating the pupil. These stereoscopic color images compare favorably with a retinal specialist exam, and can accurately diagnose retinopathy long before symptoms appear and in locations where access to ophthalmology care may be limited. Surprisingly, in more than 50 percent of patients with diabetes who do not have retinopathy, the JVN identifies eye disease that needs evaluation.
Collaborating for a Cure
Building on their earlier findings—that VEGF is elevated in retinal and ocular fluids in people with diabetic retinopathy—Joslin eye-research investigators are collaborating with Joslin colleagues on a number of projects. The collaborative approach is also undertaken at the national level via the Diabetic Retinopathy Clinical Research Network, a National Eye Institute-sponsored network of over 100 U.S. sites dedicated to rigorous clinical trials of new therapeutic approaches for diabetic retinopathy and diabetic macular edema. The section co-head is the founding Network Chairman for this initiative.