People with obesity and type 2 diabetes are at high risk of blood vessel damage. This risk depends not only on the genes a person carries, but also on how they are “read”. By changing the epigenetic reading signals in the thin fat layer surrounding arteries and veins, researchers led by the University of Zurich were able to reduce inflammation and improve blood vessel health in both mice and human tissue.

Fat that surrounds blood vessels is more than just passive padding. Known as perivascular fat, it constantly exchanges chemical signals with the vessel wall, helping to regulate how easily a vessel relaxes and how much the inner lining becomes inflamed. In healthy people, this exchange maintains smooth circulation. In obesity and metabolic disease, however, the cellular communication often shifts: the fat becomes inflamed, begins storing excess lipids differently, and releases molecules that make vessels stiffer and less responsive.

Rewriting cellular neighborhood exchange
Over time, these changes contribute to the early stages of vascular disease, which can lead to heart attacks and strokes. Researchers at the University of Zurich (UZH) and the University Hospital Zurich, collaborating with colleagues at the University of Pisa in Italy, have now succeeded in correcting the error upstream by targeting the molecular switches that determine which genes in the perivascular fat cells are turned on or off.

These epigenetic regulators are chemical tags on the proteins that package DNA. The proteins that recognize these tags determine how the genome is “read” in each cell, activating or deactivating many genes at the same time. “Instead of targeting one downstream molecule at a time, we aimed to retune the fat’s entire gene activity program,” says UZH cardiologist and study head Francesco Paneni.

Targeting gene “readers” and enzyme
In lab tests using mice and human tissue, the researchers used specific epigenetic drugs – known as BET protein inhibitors – to modulate gene expression in perivascular fat. These drugs shifted the fat’s gene-expression program away from inflammation and reduced multiple harmful processes at the same time. Blood vessels surrounded by the reprogrammed fat relaxed more easily and showed fewer signs of vascular damage when examined in tissue samples.

The researchers also identified a key driver of these effects: an enzyme called hexokinase 2, which plays an important role in sugar metabolism. When this enzyme is overactive in perivascular fat, fat cells store more fat, release more inflammatory signals, and produce substances that damage the vessel lining. “Lowering the enzyme’s activity, either indirectly by altering the epigenetic readers that control its gene or directly on the enzyme itself, blunted the fat’s inflammatory behavior and restored normal vessel function in the samples we studied,” says Paneni.

From treating symptoms to reprogramming tissue
According to the researchers, these findings could help reshape the way medicine approaches the prevention of vascular complications in people with obesity and metabolic disease. Epigenetic drugs could complement existing therapies and potentially lower the risk of early vascular dysfunction progressing to heart attacks or strokes. “Instead of solely treating downstream risk factors such as high blood pressure, cholesterol or blood sugar after damage has already begun, epigenetic therapies aim to reprogram the tissue processes that contribute to vascular damage,” says Francesco Paneni.