Bhupesh Singla, PhD, a vascular biologist in the University of Tennessee Health Science Center College of Pharmacy’s Department of Pharmaceutical Sciences, was awarded a $2.8 million grant from the National Institutes of Health (NIH) to investigate the mechanisms responsible for the development of occlusive arterial disorders, including atherosclerosis and intimal hyperplasia.

Despite available lipid-lowering drugs and ongoing research identifying novel therapeutic targets and effective treatments, atherosclerosis remains a significant unmet medical issue.

Dr. Singla’s laboratory utilizes innovative tools ranging from in vitro cell-based assays, ex vivo experiments, and molecular biology techniques with multiple genetically engineered mouse models with lineage-tracing capabilities and in vivo gene transfer. The current focus of his lab is to explore how a family of proteins, matricellular proteins, influence the development of cardiometabolic diseases.

Most research so far has focused on the mechanisms driving the deposition of lipids and immune cells in the blood vessel wall, while largely overlooking how these substances/cells can be effectively drained from the vessel wall. Lymphatic vessels in the outer layer of arterial walls are pivotal for removing cholesterol and immune cells from atherosclerotic vessels. Enhancing lymphatic function has been shown to reverse atherosclerosis, which may be a promising avenue for therapeutic intervention for this vascular disease.

Singla’s team will study the role of a matricellular protein, R-spondin 2 (RSPO2), whose levels are elevated in diseased arteries compared to healthy ones. Previously, Singla and colleagues demonstrated that applying RSPO2’s decoy receptor to the outer layer of blood vessels in atheroprone genetically modified mice reduces atherosclerosis and promotes drainage of cholesterol from arteries to lymph nodes via lymphatics. Importantly, they found increased arterial lymphatic vessel density in treated mice, suggesting the therapeutic potential of modulating this pathway.

With the new funding, Dr. Singla’s research group will examine the specific role of vascular smooth muscle cells in secreting RSPO2 and its effect on lymphatic vessel density, function, and development of atherosclerosis. The research will involve advanced mouse models, gene therapy (mouse), pharmacological inhibitors, and single-cell RNA sequencing. Further, the team will evaluate whether blocking this pathway in mice with established atherosclerosis can reduce the severity of the disease.