Alcohol Regulation of Endothelial Plasticity in Atherosclerosis

University Of Rochester, Rochester NY

Investigators

Abstract

Abstract Cardiovascular disease is the leading cause of death globally. Studies show that low-to-moderate alcohol consumption is protective against cardiovascular disease, whereas heavy binge drinking and chronic abuse is harmful. Currently lacking, however, is in-depth knowledge of the mechanisms involved. In particular, understanding the cell and molecular processes mediating the protective effects of alcohol is of great interest and could lead to novel therapies for cardiovascular disease. Most of the problems associated with cardiovascular disease are caused by arteriosclerosis, a thickening and stiffening of artery walls, that may lead to blood flow blockage resulting in heart attack or stroke. Arteriosclerosis develops in areas where the endothelial lining becomes activated or damaged in response to injurious stimuli. Emerging evidence suggests that endothelial cells, by undergoing a change in phenotype to a myofibroblast in a process known as endothelial-to-mesenchymal transition (EndMT), may themselves be key drivers of arteriosclerosis. This raises the exciting possibility of a novel cell mechanism involved in vascular pathology. Crucially, no information exists as to whether alcohol, a known modulator of cardiovascular disease, might regulate EndMT in this context, a question of considerable interest and the focus of our exploratory proposal. We have previously reported that daily moderate alcohol (EtOH) consumption reduces arteriosclerosis, while heavy binge consumption worsens it, and that EtOH stimulates Notch signaling in vascular endothelial cells. Our recently published study and our preliminary data demonstrate that EtOH at moderate levels acts to maintain endothelium in a beneficial ‘non-activated’ state. Moreover, our preliminary data are suggestive of a j- shaped relationship between EtOH and transforming growth factor-beta (TGFb)-induced EndMT of arterial endothelial cells, with lower doses of EtOH inhibiting and higher doses stimulating EC transition. Thus, the overall hypothesis of our proposal is that low-moderate alcohol consumption prevents endothelial activation, limiting EndMT in a Notch-dependent manner, thus, maintaining vessel homeostasis and protecting against arteriosclerosis, whereas binge drinking increases endothelial activation resulting in greater EndMT and exacerbated lesions. We will use human endothelial cells exposed to atherogenic stimuli in vitro, in combination with single cell RNA-sequencing (scRNA-seq) analyses of endothelial cells from a mouse model of arteriosclerosis to test our hypothesis and elucidate the mechanisms involved. Our novel study will illuminate how ‘healthy’ and ‘harmful’ alcohol consumption differentially impacts arteriosclerosis by affecting endothelial cell plasticity. These data potentially have important clinical implications with regard to prevention, treatment, and regression of cardiovascular disease.