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

摘要 心血管疾病是全世界死亡的主要原因。流行病学研究表明， 酒精和心血管疾病之间的联系，经常低至中度消费， 保护，而严重的暴食和慢性虐待是有害的。然而，目前缺乏的是深入 关于不同酒精水平如何影响动脉细胞以最终决定血管的机械知识 病理学和疾病进展。大多数与心血管疾病相关的问题开始， 动脉硬化，动脉壁增厚和硬化，可能发展为斑块， 血流阻塞导致心脏病发作或中风。动脉炎包括中膜和内膜增生 (i.e.,内膜-中膜增厚或IMT），这是由于“血管平滑肌样”a-SMA+细胞的积累。 新出现的证据表明，在对炎症或血流紊乱等有害刺激的反应中， 内皮细胞可以转化成不同的细胞类型，特别是肌成纤维细胞， 内皮-间充质转化（EndMT），从而导致内膜-中膜增厚。关键是， 关于酒精消费，一种常见的可改变的行为和一种已知的调节剂， 心血管疾病，可能会调节内皮细胞转化在这种情况下，一个相当大的问题， 我们的建议和关注点。基于我们在人类动脉细胞和 在小鼠模型中，我们将使用体外和体内功能获得和丧失方法，结合多种方法， 彩色“五彩纸屑”报告基因谱系追踪和单细胞RNA测序分析，以检验我们的假设， 酒精对致动脉粥样硬化刺激诱导的内皮细胞表型转化具有双相作用， 差异影响血管稳态和动脉硬化，并阐明Notch参与 调解这些反应。产生的数据将显著增加我们对基础科学的理解， 饮酒会影响心血管疾病，这些信息可以用来指导新的治疗方法。 发病率和死亡率的主要原因。

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.