Link Between Diabetes and Arterial Restriction Could Lead to New Treatments

Diabetes

One of the major complications of diabetes is narrowing of the blood vessels. This constriction increases the risk of heart disease and stroke. Researchers at UC Davis Health identified a new molecular link that could potentially lead to new diabetes treatments and potential cardiovascular therapies. They published their research in The Journal of Clinical Investigation.

The same group had previously discovered that hyperglycemia—high blood sugar—activated an enzyme called protein kinase A (PKA). PKA increases calcium channel activity, resulting in constricting blood vessels.

“This was a surprise, since PKA is typically associated with blood vessel widening and wasn’t really on our radar,” stated senior author Manuel Navedo, professor of pharmacology at UC Davis Health. “We wanted to understand the molecular processes that created this opposite reaction.”

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Navedo and his research team studied the effects of high blood sugar on cerebral blood vessels and arterial cells that are involved in the control of blood flow. They studied genetically modified mice and mouse models of diabetes developed at UC Davis for cardiovascular research.

The research examined the relationship between PKA and adenylyl cyclase (AC), an enzyme involved in the production of cyclic AMP (cAMP), a cellular messenger that plays a critical role in vascular cell function.

The researchers found that AC5, which mediated cAMP and PKA activation, caused increased calcium channel activity, resulting in narrowing of the blood vessels. They also discovered that AC5 was required for blood-vessel constriction during diabetes.

The next step in their research will be to study the effects of the AC5 chain reaction in high-blood-sugar conditions in human cells. They speculate that it has potential as a treatment target for decreasing the vascular complications of diabetes, which can cause eye, kidney, brain, gastrointestinal and cardiovascular disease.

“We see every day in our clinics the devastating impact of diabetes on the health and lives of our patients,” stated co-author Nipavan Chiamvimonvat, the Roger Tatarian Endowed Professor in Cardiovascular Medicine at UC Davis Health. “Our work brings into much clearer focus on how high glucose can damage the vascular system and gives us a new target for blocking its effects.”

In a post on the Society for Vascular Surgery website, Gregory Moneta, a member of the society and professor and chief of vascular surgery at Oregon Health and Science University Knight Cardiovascular Institute, says, “Diabetes is one of the strongest risk factors for any form of vascular disease, both symptomatic and asymptomatic. Those with diabetes should have regular doctor visits and tests, and may need to see specialists such as ophthalmologists, vascular surgeons and podiatrists for checkups.”

The society lists six vascular complications that are aggravated by diabetes. They include diabetic eye disease, peripheral artery disease (PAD), foot ulcers and peripheral neuropathy, complications from smoking, heart attack, and renovascular conditions, which can lead to kidney failure and the need for dialysis or a kidney transplant.

The most common type of PAD is atherosclerosis, which is the buildup of fats and cholesterol in the arteries, which further restricts blood flow.

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