Novel mechanisms and vascular interactions mediating the cardiometabolic benefits of exercise

Cardiovascular diseases, including coronary artery disease, stroke, and peripheral arterial disease predispose individuals to develop chronic disability, compromise life quality and increase burden on the healthcare system. Physical exercise modulates metabolic processes in multiple organs to ameliorate cardiovascular disorders. After decades of exercise research, there is still incomplete understanding of the molecular changes elicited by exercise training. Individuals with physical disabilities and/or living in unfavorable living conditions face multiple challenges to engage in regular physical activity; therefore, there is a need to develop therapeutic interventions that mimic the effects of exercise for vascular protection. Endothelial cells in the inner layer of blood vessels have been traditionally thought to primarily consume glucose through anaerobic glycolysis; however, recent studies demonstrated that active formation of lipid droplets in the endothelium of large vessels predisposes to atherosclerosis and high blood pressure. Our overarching hypothesis is that exercise modulates endothelial lipid metabolic pathways to maintain anti-inflammatory properties in the vascular endothelium. We will test our hypothesis in 2 aims: in Aim 1, we will develop “exercise in a dish” approaches integrating multiple cell types and mechanical forces to recreate the physiological microenvironment. We will combine molecular and cell biology, imaging and metabolomic analysis to identify molecules targeting lipid droplet biogenesis and/or lipolysis to prevent lipid accumulation, and we will test whether exercise performance in mice prevents lipid droplet accumulation. In Aim 2, we will investigate the role of exercise-induced metabolites in the modulation of G-protein coupled olfactory receptors expressed ectopically in the blood vessels. Overall, the long-term goal of our project is to identify pathways leading to therapeutic interventions that have the same effects as exercise for vascular protection. The SuRE support will contribute to the growth of research at Charles R. Drew University of Medicine and Science.