It has been known for some time that atherosclerotic lesions preferentially develop in areas exposed to low SS and are characterized by a proinflammatory, apoptotic, and senescent endothelial phenotype. Conversely, areas exposed to high SS are protected from plaque development, but the mechanisms have remained elusive. Autophagy is a protective mechanism that allows recycling of defective organelles and proteins to maintain cellular homeostasis. We aimed to understand the role of endothelial autophagy in the atheroprotective effect of high SS. Atheroprotective high SS stimulated endothelial autophagic flux in human and murine arteries. On the contrary, endothelial cells exposed to atheroprone low SS were characterized by inefficient autophagy as a result of mammalian target of rapamycin (mTOR) activation, AMPKα inhibition, and blockade of the autophagic flux. In hypercholesterolemic mice, deficiency in endothelial autophagy increased plaque burden only in the atheroresistant areas exposed to high SS; plaque size was unchanged in atheroprone areas, in which endothelial autophagy flux is already blocked. In cultured cells and in transgenic mice, deficiency in endothelial autophagy was characterized by defects in endothelial alignment with flow direction, a hallmark of endothelial cell health. This effect was associated with an increase in endothelial apoptosis and senescence in high-SS regions. Deficiency in endothelial autophagy also increased TNF-α–induced inflammation under high-SS conditions and decreased expression of the antiinflammatory factor KLF-2. Altogether, these results show that adequate endothelial autophagic flux under high SS limits atherosclerotic plaque formation by preventing endothelial apoptosis, senescence, and inflammation.

中文翻译：

---

在生理性血流下自噬是内皮细胞排列和动脉粥样硬化保护所必需的

一段时间以来已知动脉粥样硬化病变优先在暴露于低SS的区域发展，其特征在于促炎，凋亡和衰老的内皮表型。相反，可以保护暴露于高SS的区域免于噬菌斑的形成，但是其机制仍然难以捉摸。自噬是一种保护机制，可回收有缺陷的细胞器和蛋白质以维持细胞稳态。我们旨在了解内皮自噬在高SS的抗动脉粥样硬化保护作用中的作用。防动脉粥样硬化的高SS刺激人和鼠动脉中的内皮自噬通量。相反，由于哺乳动物对雷帕霉素（mTOR）的激活，AMPKα抑制，并阻止自噬通量。在高胆固醇血症小鼠中，内皮自噬的缺乏仅在暴露于高SS的抗动脉粥样硬化区域增加了斑块负担。斑块的大小在动脉粥样硬化区域中没有改变，在该区域中，内皮自噬通量已经被阻断。在培养的细胞和转基因小鼠中，内皮自噬不足的特征是内皮与流动方向的对齐缺陷，这是内皮细胞健康的标志。这种作用与高SS区内皮细胞凋亡和衰老的增加有关。在高SS条件下，内皮自噬的缺乏也增加了TNF-α诱导的炎症，并降低了抗炎因子KLF-2的表达。共，