Biphasic Regulation of Endothelial Transdifferentiation by Alcohol and Its Impact on Vascular Disease

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Abstract Cardiovascular disease is the leading cause of death worldwide. Epidemiological studies indicate a biphasic association between alcohol and cardiovascular disease with frequent low-to-moderate consumption being protective, whereas heavy bingeing and chronic abuse is harmful. Currently lacking, however, is in-depth mechanistic knowledge of how different levels of alcohol impact arterial cells to ultimately dictate vessel pathology and disease progression. Most of the problems associated with cardiovascular disease begin with arteriosclerosis, a thickening and stiffening of the artery wall, that may progress to plaque development and blood flow blockage resulting in heart attack or stroke. Arteriosclerosis involves medial and intimal hyperplasia (i.e., intima-media thickening or IMT) due to the accumulation of ‘vascular smooth muscle-like’ a-SMA+ cells. Emerging evidence suggests that in response to injurious stimuli such as inflammation or disturbed flow, endothelial cells can transform into different cell types, especially myofibroblasts in a process known as endothelial-to-mesenchymal transition (EndMT), and thus contribute to intima-media thickening. Crucially, no information exists as to whether alcohol consumption, a common modifiable behavior and a known modulator of cardiovascular disease, might regulate endothelial transformation in this context, a question of considerable interest and the focus of our proposal. Based on our exciting preliminary data in human arterial cells and in a mouse model, we will use gain-and-loss of function approaches in vitro and in vivo, in combination with multi- color ‘Confetti’ reporter lineage tracing and single-cell RNA-sequencing analyses to test our hypothesis that alcohol has a biphasic effect on atherogenic stimuli-induced endothelial phenotypic transformation to differentially affect vessel homeostasis and arteriosclerosis and to elucidate the involvement of Notch in mediating these responses. Data generated will markedly increase our basic science understanding of how drinking affects cardiovascular disease, information that could be leveraged to inform novel treatments for this leading cause of morbidity and mortality.