Aspirin Restores Endothelial Function By Mitigating 17 Beta-Estradiol-Induced Alpha-Sma Accumulation And Autophagy Inhibition Via Vps15 Scaffold Regulation Of Beclin-1 Phosphorylation

Aims: Previous studies have shown that the widespread use of estrogen preparations can cause adverse outcomes such as thrombosis and cardiovascular disease. Autophagy is a biochemical process necessary to maintain cell homeostasis. The present study investigated whether E-2 mediates autophagy-induced endothelial cell dysfunction. The role of aspirin in this process was then studied.Main methods: Western blot, fluorescence microscopy, electron transmission microscopy, plasma construction and transfection, vasoreactivity study in wire myograph are all used in this study.Key findings: We found that E-2 activated the PI3K/mTOR signaling pathway and inhibited the formation of the Atg14L-Beclinl-Vps34-Vps15 complex, thereby inhibiting autophagy. Aspirin promoted Beclinl phosphorylation in autophagy initiation complexes and enhanced autophagy. Furthermore, E-2 treatment of HAECs resulted in endothelial dysfunction by inhibiting autophagy and leading to accumulation of alpha-smooth muscle actin (aSMA). E-2 inhibited the activation of eNOS and reduced the expression of eNOS protein. In the mouse aortic vascular function test, E-2 disrupted endothelium-dependent vasodilation. An alpha-SMA-shRNA lentivirus eliminated the disruption to endothelium-dependent vasodilation by E-2. Aspirin inhibited alpha-SMA accumulation by enhancing autophagy, reversed endothelial functional impairment caused by E-2, and promoted endothelium-dependent vasodilation.Significance: This study provides new evidence that E-2 inhibits autophagy and induces abnormal accumulation of alpha-SMA, resulting in endothelial cell dysfunction and affecting vasodilation. Aspirin can effectively restore the endothelial cell function disrupted E-2.