Study discovers how diabetes leads to vascular disease

A team of scientists and physicians identified a cellular connection between diabetes and one of its major complications - narrowing of the blood vessel - which increases risks of several serious health conditions, including heart disease and stroke.

The same team previously found that high blood glucose, the hallmark symptom of diabetes, activates an enzyme known as protein kinase A (PKA), which increases calcium channel activity and constricts blood vessels.

"This was a surprise since PKA is typically associated with blood vessel widening and wasn't really on our radar. We wanted to understand the molecular processes that created this opposite reaction," said senior author Manuel Navedo.

For the new study, published in the journal of Clinical Investigation, the team conducted a series of experiments on the effects of high glucose on cerebral blood vessels and arterial cells that control blood flow. The tests were conducted on a unique genetically modified mouse and two mouse models of diabetes that were developed for studies of cardiovascular health.

The researchers focused on the relationship between PKA and adenylyl cyclase (AC), an enzyme involved in cyclic AMP (cAMP) production, a cellular messenger with a critical role in vascular cell function.

Their results showed that one AC in particular, AC5 mediated cAMP and PKA activation, triggering increased calcium channel activity and blood vessel narrowing. They also found that AC5 was essential for blood-vessel constriction during diabetes.

The team now hopes to test the effects of the AC5 chain reaction in high-glucose conditions in human cells. This step could confirm it as a treatment target for reducing the vascular complications of diabetes, which can include eye, kidney, and cerebral, gastrointestinal and cardiovascular disease.

"We see every day in our clinics the devastating impact of diabetes on the health and lives of our patients. 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," said co-author Nipavan Chiamvimonvat.