Many vascular diseases such as atherosclerosis and pulmonary hypertension are irreversible. While factors like high cholesterol, smoking, and lack of exercise can add to the risk of increased injury, once the disease is established it becomes a self-sustaining process that progresses even if the patient reduces cholesterol level, quits cigarettes, or increases physical movement. A new study uncovers the metabolic basis underlying vascular disease and insights for reversing once incurable diseases. A key process perpetuating the long-standing tissue inflammation that drives vasculature disease is known as endothelial-to-mesenchymal transition (EndMT). Through this process, the cells lining the insides of blood vessels—known as endothelial cells—undergo a change in phenotype and begin expressing gene markers that trigger the chronic inflammation. A team led by Michael Simons, MD, professor of medicine (cardiology), identified the metabolic basis for EndMT and a key player in this process—an enzyme called ACSS2. Importantly, the researchers further found that knocking out this enzyme dramatically reduced the development of atherosclerosis—an EndMT-driven disease—in mice. They published their findings in Cell Metabolism on June 15. We now uncovered ... why these diseases become stimulus-independent, and we show that if we remove this underlying driver, we can reverse intractable illnesses and effectively treat people in ways that do not exist in the present.Michael Simons, MD “We have a group of diseases that once started, they continue to go forward even if you remove the offending stimulus,” says Simons, who was the study’s co-principal investigator with Zoltan Arany, MD, PhD, Samuel Bellet Professor of Cardiology at the University of Pennsylvania’s Perelman School of Medicine. Simons adds, “We now uncovered the molecular basis of this persistence to understand why these diseases become stimulus-independent, and we show that if we remove this underlying driver, we can reverse intractable illnesses and effectively treat people in ways that do not exist in the present.” Vascular Abnormalities Underlie Many Chronic Diseases Every organ in the body relies on the vascular system for oxygen, nutrients, and physiological maintenance. Abnormalities in the vasculature are responsible for a significant number of chronic diseases. Simons’ lab focuses on the links among vascular abnormalities, disease, and aging. His team was one of the first to discovery EndMT and its involvement in conditions including atherosclerosis, peripheral vascular disease, heart attacks, and pulmonary hypertension. EndMT triggers abnormalities in the endothelial cells that attract inflammatory stimuli including white blood cells. “Normally they would pass these cells by, but now they stop and enter the tissues and begin secreting inflammatory cytokines,” Simons explains. Importantly, once this process begins, it becomes irreversible. “All of our attempts to cure diseases with this underlying chronic inflammatory process have failed,” says Simons. EndMT is a complicated process, says Simons, because it is largely driven by TGF-β signaling, which regulates many functions within cells. “This is a very unusual signaling mechanism because while it is pro-inflammatory in endothelial cells, it’s anti-inflammatory in essentially every other cell type,” he explains. “So you cannot use systemic agents to block this process because they will do more harm than good.” Thus, it is essential for any potential therapies to target the endothelial cells themselves. Team Uncovers Metabolic Basis of EndMT Endothelial cells have an unusual metabolic profile. Normally, cells use fat as their predominant source of energy. Endothelial cells, on the other hand, mainly rely on sugar for their energy needs. Furthermore, during EndMT, endothelial cells undergo extensive gene expression changes, and it’s likely that these changes are metabolic in nature. Thus, Simons’ team became intrigued about whether there is a unique metabolic basis to EndMT, and if so, if it could provide insight on how to target EndMT. The team began by exploring the metabolic changes that TGF-β signaling induced in endothelial cells and noticed that it led to the cells making an excessive amount of a molecule known as acetyl-CoA (Ac-CoA). Intrigued, the team looked for where the Ac-CoA came from. “And here there was a big surprise,” says Arany. “Much of the Ac-CoA came from acetate.” Acetate is a very small metabolite typically generated by bacteria in the gut, and rarely used to make Ac-CoA. But in this case, the team found that acetate was made from sugar by the endothelial cells themselves, and the cells used it to make a large part of their Ac-CoA. This is important, because Ac-CoA is a major source of energy in many cell types, but in the context of EndMT, it plays a surprising role, the team found. It did not generate energy, but rather, was a source of acetyl-groups that stabilized the expression of TGF-β signaling molecules. Normal endothelial cells do not respond to the surrounding TGF-β in the blood and tissues because they express essentially no TGF-b receptor . But when excessive acetyl-groups originating from Ac-CoA bind to the TGF-β receptor, it results in a dramatic increase in its expression, thereby allowing the endothelial cells now expressing this receptor to be harmed by the noxious TGF-β stimulus. They also identified that an enzyme known as ACSS2 was essential for Ac-CoA synthesis in endothelial cells. Next, the team wanted to see if their new insights were biologically meaningful in vivo. In mice with atherosclerosis, they found that deleting the ACSS2 gene dramatically reduced the extent of the disease’s development, highlight ACSS2 as a promising target for EndMT therapeutics. “We hope to use this finding to develop new therapies and translate those therapies in vivo,” says Simons.